1 CT Department of Health and Human Services Meeting of the NATIONAL HUMAN RESEARCH PROTECTIONS ADVISORY COMMITTEE (NHRPAC) Monday, April 29, 2002 VOLUME I Hilton Washington Embassy Row Ambassador Room 2015 Massachusetts Avenue, NW Washington, D.C. 20036 2 A G E N D A Monday, April 29, 2002 AM Session 8:30-8:35 WELCOME: OVERVIEW OF MEETING Mary Faith Marshall, Ph.D. Chairperson, NHRPAC 8:35-9:00 OPENING REMARKS Edward D. Miller, M.D. Dean, Medical Faculty and Chief Executive Officer Johns Hopkins Medicine 9:00-11:00 CHILDREN'S WORKGROUP: MINIMAL RISK, MINOR INCREMENT OVER MINIMAL RISK, & DISORDER/CONDITION Alan Fleischman, M.D. Chair, Children's Workgroup Senior Vice President The New York Academy of Medicine [10:15-10:30] Break 11:00-11:15 CLASSIFIED RESEARCH -- UPDATE Greg Koski, M.D., Ph.D. Director, Office of Human Research Protections 11:15-12:00 HIPAA: NHRPAC RESPONSE TO HHS NPRM AMENDING THE FINAL HIPAA REGULATION Mark Barnes, J.D., LL.M. Partner Ropes and Gray 12:00-1:00 LUNCH 1:00-1:30 PESTICIDE TESTING IN HUMANS -- UPDATE ON HUMAN STUDIES ISSUES AT EPA William Jordan, J.D. Senior Policy Advisor Office of Pesticide Programs Environmental Protection Agency PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 3 AGENDA - Continued 1:30-3:00 PESTICIDE TESTING IN HUMANS -- OTHER PERSPECTIVES Moderator: Mary Faith Marshall Richard Wiles Senior Vice President Environment Working Group Howard Sandler, M.D. President Sandler Occupational Medical Associates, Inc. Russell Katz, M.D. Director of Neuropharmacologic Drug Products Center for Drug Evaluation and Research Food and Drug Administration 3:00-3:00 TBD 3:30-3:45 Break 3:45-5:30 UPDATE: INFORMED CONSENT -- DISCUSSION OF THREE ISSUES: Elliot Dorff, Ph.D. Co-chair workgroup 5:30 Adjourn 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: 8:30 a.m.] 3 CHAIRPERSON MARSHALL: Good morning. Thank 4 you all for being here. Welcome to NHRPAC. We are 5 very much in the news these days. I'm sure everyone 6 has seen or perhaps saw the April 22nd issue of "Time 7 Magazine" with its strange -- I don't know whether it's 8 an unfortunate cover, but I'm sure it captured 9 attention. 10 So we have important business before us and 11 important business to do. And we are going to move 12 sort of straight into our agenda because we have a 13 packed day. 14 I do want to just inform you of one slight 15 schedule change, and that is, at 8:15 when we're 16 scheduled for our break we are going to give -- 10:15, 17 I'm sorry. 18 [Laughter.] 19 CHAIRPERSON MARSHALL: Yes, we've had our 20 break. We are going to give Greg Koski some time on 21 the schedule because he has to leave us for just a 22 little bit, and then we will have our break at 10:30. 23 I can't tell you how delighted I am to 24 introduce to you my good friend and colleague, Ed 25 Miller, who is the Dean and the CEO -- he's the Dean of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 7 1 the Medical School at Johns Hopkins University and the 2 CEO of their Medical Center. 3 But Ed and I go back a long way. We grew up 4 together at the University of Virginia and ran the 5 surgical ICU there together for many years. It was a 6 formative experience, I think, for both of us. 7 It was, as my mentor John Fletcher likes to 8 say, the Vietnam of ICUs. We had every surgical 9 service in one ICU back then, 16 beds. Everything from 10 open heart surgery from 90-year-olds to one-day-old 11 patients, to trauma. If you had surgery and were sick 12 you came to our unit. And we were very proud of 13 ourselves. We sort of considered ourselves the Navy 14 Seals of the critical care world because we knew it all 15 and could do it all and cracking chests was just, you 16 know, nothing. It was passe for us. 17 [Laughter.] 18 CHAIRPERSON MARSHALL: But I will tell you 19 the whole time that I was there in the unit, I think 20 the most exciting day we had was the day that Ed was 21 attending. It was the first time that I had ever seen 22 anyone perform a cricothyroidotomy in the unit. So I 23 can tell you that he has good hands. And not only does 24 he have good hands, but he has a good mind and a good 25 heart. And, Ed, thank you so much for being here. We PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 8 1 are just delighted and honored to have you. 2 DR. MILLER: Thanks. 3 As said, Mary Faith and I go back longer than 4 we like to talk about, but it was -- "formative" is 5 correct, is the only way to say it. 6 What I would like to do this morning is talk 7 a little about our experience at Johns Hopkins which 8 has been in the news. 9 On June 2, 2001, Ellen Roche, who was a 24- 10 year-old lab technician working at Hopkins, died after 11 participating in a human volunteer -- as a human 12 volunteer in an asthma study. And, of course, this is 13 everyone's worst nightmare. 14 What I would like to do today is to kind of 15 set the framework about what went on, so you have some 16 facts, which doesn't always come out; and secondly, 17 what we did; third, where are we now; and fourth, where 18 are we going and give some time for some questions and 19 answers. 20 Greg and I have been on many panels together 21 and so this is not news to him at all. 22 Now, first, let me just tell you a little bit 23 about Johns Hopkins. For those of you that are not 24 familiar, it's a very large institution. 25 Johns Hopkins Medicine has the hospital and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 9 1 health system and the school of medicine are combined 2 into this one entity with one Dean CEO. It has three 3 hospitals. It has the Johns Hopkins hospital, it has 4 the Bayview hospital which is the old Baltimore City 5 Hospital that has been totally reconfigured and brand- 6 new, and we also have Howard County General Hospital. 7 We see about 1.5 million outpatient visits a 8 year. We have over 80,000 discharges. We have a $2.5 9 billion budget, we have $600 million in research, and 10 we have a faculty greater than 2,000. So it's a very 11 large, big, complex organization. 12 And in terms of clinical research, we do 13 about 2,600 clinical trials are open at any one time. 14 And in the year we have about 50,000 patients enrolled 15 and admittedly a tremendous increase in the number of 16 studies that go on there over the last ten years. 17 Let me tell you about the study in which 18 Ellen died in. It was an NIH-funded study. It was to 19 be done of human volunteers. These are healthy 20 individuals who did not have asthma. And we were 21 looking at the mechanisms responsible why some people 22 get severe bronchospasm and then are able to relax 23 their lungs, so to speak, while others cannot. 24 We were going to do something new and 25 different in the study. Three previous studies had PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 10 1 been done in the '80s using a similar technique, but 2 there were some nuances to this study. 3 Number one, we were using a substance called 4 hexamethonium which had been a drug in the '60 which 5 actually is a ganglionic blocker known to 6 anesthesiologists and people that treat hypertension, 7 by the way. 8 Secondly, we could measure nitric oxide, a 9 substance that was not known when the studies in the 10 '80s were done or just starting to be recognized, and 11 the idea was to look at non-antigenic, non-cholinergic 12 nerve fibers of the lung. That is, some extra nerves 13 that innervate the lung. And what we would do is we 14 would challenge these healthy volunteers with a 15 substance that would -- methacholine which would give 16 them some broncho constriction and then we would either 17 pre-treat or treat afterwards with hexamethonium, a 18 gram of it, which is inhaled. 19 Ellen consented to participate in the study 20 on April 16, 2001. She actually had participated in 21 other studies, and, as most of you know, many human 22 volunteers are on panels. And she was in one of the 23 panels. She had filled out, kind of, who she was and 24 the things that she did and the areas that she was 25 interested in and so she was in a databank along with a PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 11 1 significant number of people so that when studies came 2 along we could go to the databank and ask volunteers if 3 they wanted to participate. 4 She was the third patient in the study. The 5 first patient was started on April 23rd and underwent 6 the study with inhaling a gram of hexamethonium. And I 7 should point out that that first patient had some cough 8 and some shortness of breath which was followed -- 9 thought by the clinician to be just a URI, an upper 10 respiratory tract infection, and actually the symptoms 11 went away. And, as a matter of fact, were gone prior 12 to her study. 13 On May 4th Ellen started the study. She 14 inhaled a gram of hexamethonium. On May 5th she had a 15 dry cough. And then on May 9th she was admitted to the 16 hospital because of increasing shortness of breath. On 17 May 12th things got much worse. She was taken to the 18 intensive care unit, intubated, ventilated, and over 19 the next 15, 16 days, she had a progressive down-hill 20 course whereby she died from multi-organ system 21 failure, coagulopathy, liver renal failure, and 22 ultimate lung failure. And on June 2nd, she died. 23 Well, as I say, this is the worst nightmare 24 that you can imagine; a healthy human volunteer who 25 comes into a study and these are events that you never PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 12 1 anticipate will occur. 2 Well, what did we do? Well, as soon as we 3 knew there was trouble with this patient or volunteer, 4 excuse me, we stopped all human volunteer studies at 5 Hopkins. We had informed OHRP and the FDA that we had 6 a patient in trouble and we kept them informed of where 7 we were and what was happening. 8 Well, when she died we immediately formed an 9 internal review committee that had total access to all 10 the data. We asked them to be as critical of our 11 processes as possible so that we would have all of the 12 information and that we could present the information 13 as factually as possible. And I guess I want to 14 emphasize that because there was a tremendous pressure 15 from the press to get information out to the public and 16 we didn't have all the information. 17 And, secondly, we had tremendous pressure 18 from the family not to release any information 19 whatsoever. But we had, really, the Baltimore Sun 20 constantly coming at us which is a very difficult issue 21 to deal with. 22 On July 16th, we had a press conference and 23 we had the report available from the internal review 24 committee. And the report I will just summarize by 25 some of the significant points. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 13 1 First, they thought her death was probably 2 related to hexamethonium but it could not be proved. 3 It was just -- there wasn't anything that we could say 4 that it wasn't due to, but there wasn't proof perfect. 5 Secondly, that the review committee -- 6 internal review committee -- was very concerned that 7 the first subject who had the cough had not been 8 reported by the investigator to the IRB, and should 9 have done that. 10 Now, I want to point out that in the 1980s a 11 similar study was done at the University of California 12 in San Francisco. They also had a subject who had a 13 cough, was worked up extensively by an internist -- 14 pulmonologist -- who was removed from the study and 15 decided that it was not related to this. But that did 16 not appear in the report that was published. So the 17 investigators had not heard of any complications. 18 Third is that there were small changes in the 19 protocol that were not reported. The difference 20 between saline and water is the diluent for the 21 administration of the hexamethonium. 22 Fourth that the literature review was not 23 complete. Our investigator did a typical Medline 24 search of the literature. If he had put in to Yahoo, 25 "hexamethonium lung disease" old literature in the '50s PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 14 1 would have popped up. 2 Now, let me point out that that drug, 3 hexamethonium, which at that time was a drug, was 4 infused intravenously or given very large doses in 5 patients with very severe pulmonary hypertension to 6 treat -- and systemic hypertension, and that's why the 7 drug was used. And the pulmonary complications in 8 those case studies were all related to long-standing 9 administration of very high doses of the drug not given 10 by inhalation. 11 The internal review committee was very 12 critical of the fact that hexamethonium was not a drug. 13 It had been a drug in the '60s, had been pulled off 14 the market because it was not effective as some of the 15 newer anti-hypertensive agents and we did not have FDA 16 clearance to use this. And this we can talk a little 17 bit about the problem that we have in terms of 18 substances that are not new drugs, they're substances 19 that we want to look at mechanisms in human physiology 20 or pathophysiology and we need some way to get some 21 clarification. 22 And then last, and probably most importantly, 23 there was a sense from the report that the IRB had not 24 been as critical as it could be. 25 On July 16th, that afternoon that the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 15 1 external -- the internal report was released to the 2 press, OHRP came in, and in the afternoon at 1:00 we 3 had an entrance interview. They examined this case, 4 they found some other cases, Tuesday, Wednesday, and 5 then Thursday morning OHRP came in and you have to 6 imagine in the board room one side OHRP, Hopkins on the 7 other side, not a very interesting or enjoyable time 8 for anybody in that room. And they essentially read to 9 us the findings that they were concerned about and at 10 the end said, all of your clinical trials are closed 11 down as of this time. 12 Now, we have 50,000 people in clinical 13 trials, including people that are undergoing bone 14 marrow transplants and, you know, new drugs, et cetera, 15 et cetera. 16 So we closed down all the trials. We were, I 17 will say, shocked at the response from this. But over 18 the weekend we worked with OHRP and Greg and I were in 19 constant contact, we revised a variety of procedures 20 and then over the next four to five months we 21 rereviewed all 2,600 protocols and by mid-December we 22 were up and running and in many of the studies we were 23 up and running earlier than that because of rapid 24 review of these protocols and for patients that needed 25 to be in these protocols. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 16 1 I will say OHRP said, "do no harm" in 2 shutting these patients down, make sure that we were -- 3 making sure that patients who were in critical 4 protocols continued in those while some of the other 5 ones we could move more slowly on. 6 At the same time we had an external review 7 committee come in because we didn't want anybody to 8 think that our internal review was mild-mannered. So 9 we had both the internal, OHRP, the FDA, and then the 10 external review committee and I cay say they 11 essentially said that the consent form was grossly 12 inadequate because it did not point out that the 13 hexamethonium was no longer a medication but rather a 14 substance. There was not any idea that there was a 15 possibility of death on the consent form. But, more 16 importantly, they felt that our review of protocols was 17 grossly inadequate and not to the current standards. 18 And let me just say that Hopkins had been 19 working with OHRP in trying to look at how we did it, 20 and our system had been different than others and it 21 had served -- we thought had served us well. 22 We would review -- we would take a protocol 23 and we would get three or four experts in the area to 24 review the protocol. That subcommittee then would 25 bring it to the big board and often the big board would PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 17 1 have a few comments, but the real substance was done at 2 the small group which is not adequate for the rules and 3 regulations that OHRP had set forth. 4 Well, what did we do? First I would say that 5 we changed our attitude from really a combative 6 relationship between OHRP and probably -- that's 7 probably too strong a word. I wouldn't say "combative" 8 I would say there was no communication, no way to talk 9 between the two sides about what we could do to move 10 forward. And as I said, we worked very hard over the 11 weekend and we actually worked very hard over the last 12 nine to ten months to make sure that OHRP, the FDA, and 13 Hopkins are all kind of in the loop in where we're 14 going because these are tough areas. These are not 15 easy area. 16 We have gone from two IRBs, actually, to six. 17 We have spent about a million dollars in this in the 18 past. We now spend two in infrastructure. I have a 19 new vice dean for clinical investigation, Mike Clagg, 20 who has a long history in clinical investigation. The 21 infrastructure is significantly improved and the number 22 of people there to make sure that we have all the 23 processes in place are correct, and we have worked with 24 a western IRB, a for-profit IRB, to take a look at: 25 Number one, can they help us in finding PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 18 1 people for our infrastructure? 2 Secondly, can they help us review those 3 multi-centered studies that perhaps they review because 4 they do it across so many different places, and so we 5 have used those. 6 Well, what has been the most difficult? 7 Well, I will tell you the most difficult, of course, 8 was talking to Ellen's father. He, himself, had been a 9 human volunteer, so he understood the studies. And I 10 met with him before the internal report was released 11 and I've actually met with him subsequently. He's a 12 wonderful person, actually, and has actually no 13 animosity toward Hopkins, but how can we make the 14 system better? 15 The most difficult and second most difficult 16 has been dealing with the press. And I have to say, 17 that has been really tough. They are always at you and 18 they were really pushing very hard and they would 19 literally walk into the hospital and start talking to 20 people before we had all of our data put together. And 21 we finally just said, this has got to stop because it's 22 really damaging to everyone and especially the family. 23 But, you know, the press is the press. 24 What good has come out if it? Well, 25 certainly I think we have changed our culture. We PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 19 1 certainly have a culture of compliance now. And I will 2 say that it cuts across not only in clinical 3 investigation, but animal care, grants and contracts, 4 billing, et cetera, et cetera. 5 Everybody understands that we definitely have 6 to have compliance in place to move forward and we've 7 got to do it as best we possibly can. 8 There has not been a fall-off in the studies. 9 Patients and subjects still come to Hopkins, and so we 10 continue to work very hard in that area. 11 So what are some of my suggestions, or what 12 did we learn? 13 Well, first, I said, we have used this as a 14 wake up for everybody, that we have to make sure that 15 we are compliant, we have to make sure that we have the 16 best processes in place. Because it's hard to say 17 this, but even if we had all of the things in place, 18 even if we had known the literature review, even if the 19 first patient we knew about it and we had looked at it 20 because everything got better, we probably still would 21 have gone ahead with that study and we could have still 22 had the same effect, but we didn't have all the "t"s 23 crossed and all the "i"s. We didn't do everything 24 humanly possible. And, therefore, you know, we have to 25 accept the blame for that. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 20 1 We have training for our faculty. I was 2 mentioning to Greg, you know, it's easier to get a 3 driver's license than -- or harder to get a driver's 4 license than to become a clinical investigator because 5 there is really -- the training is pretty slipshod, I 6 would say. You kind of always learn from the person 7 ahead of you and so we have put together a very 8 extensive orientation for our new faculty that are 9 being involved and our current faculty, we do give a 10 masters and a Ph.D. in clinical investigation and have 11 had that for years. But you can imagine the number of 12 investigators that are involved, they don't all enroll 13 in all of these programs. But we have put a variety of 14 modules in place so that we cover the various aspects 15 that we need to. And, we have put additional resources 16 into that. 17 We have used the for-profit IRB model for 18 some studies, and I think we have to look closely about 19 how that works, especially for large drug studies 20 sponsored by pharmaceutical industries that cover 20, 21 30, 50 centers. Do they all have to be reviewed by the 22 individual centers? That's a question that I think is 23 on the table. 24 The issue of using volunteers that come from 25 your own institution. The external report was critical PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 21 1 that there was perhaps coercion of the patients -- of 2 the subjects that enrolled. We didn't think so. We 3 hadn't really thought about it that way because so many 4 people want to work at Hopkins, we are the largest 5 private employer in Maryland. People come and work at 6 medical centers for a variety of reasons, they want to 7 make a difference and they feel they can participate in 8 studies, but Ruth Vaden and her people are a group 9 looking at this so we can get an opinion. 10 And then, lastly, I guess the question is, 11 what are we going to do about certification of clinical 12 investigators? And I think there could be grades of 13 certification for simple studies, and more complex and 14 so forth, who is going to pay for it, how could you do 15 it, it would be in the best interest of the large 16 pharmaceutical industries to do it. What you see in 17 the pharmaceutical industry is 10 to 12 new drugs or 18 new compounds in the early stages of testing in man. 19 That is a dramatic increase of just over 20 three or four years ago when people were dealing with 21 one or two. So if you multiply that times the 22 pharmaceutical industry, you've got this tremendous 23 number of potential drugs coming down the line with a 24 very limited number of clinical investigators, how do 25 we increase this? They would be well to have some kind PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 22 1 of funding pool so that we could increase that. 2 So those are some of the issues that we have 3 to deal with. As I say, this has been a very tough 4 time for Hopkins. There is absolutely no question 5 about it. But clinical research is incredibly 6 important. And the way I look at it is, you know, we 7 could probably either cure polio or make better 8 ventilators. I think we should cure polio and not make 9 better ventilators. And the only way we're going to do 10 that is through clinical investigation, but it has to 11 be done right, and it has to be done as safely as you 12 possibly can. And when something like this happens in 13 our institution it really, really shakes the 14 foundations. So with that, I turn it back to you. 15 CHAIRPERSON MARSHALL: Thank you, Ed, very 16 much. 17 Our pattern of running meetings is that we 18 give time to our committee members to ask questions and 19 then an equal amount of time to our public members. So 20 I know we are scheduled to go until 9:00, I think maybe 21 we could go a couple of minutes over. So let me open 22 the floor up to questions from the committee and then 23 we'll open it up to our other folks. Adil and then 24 Jonathan and then Judy. 25 DR. SHAMOO: Thank you. Thank you, Dr. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 23 1 Miller, for coming here. 2 I have two questions. One, Johns Hopkins 3 between 1990 to the year 2000 probably over 400,000 4 human subjects passed through. 5 DR. MILLER: Probably. 6 DR. SHAMOO: They reported to OHRP zero 7 deaths and only a handful, less than a doze adverse 8 events. How could that be? If you take any other 9 adverse events in hospitals, in any other setting in 10 medical care, you will have at least dozens of deaths 11 and thousands of adverse events. That's one question. 12 The second question is, part of leadership is 13 accountability and stepping forward. Hopkins in the 14 first three weeks, not only did not step forward and 15 take leadership -- moral leadership in this area, they 16 obfuscated, they did not want to release any 17 information and at times they really did not tell even 18 the truth. The press it's for the whole First 19 Amendment rights. And they serve a good purpose 20 despite all their flaws. And what has happened at 21 Johns Hopkins that indicate leadership -- leadership 22 means accountability. Who took the responsibility and 23 was held accountability for the flaws what I consider 24 for the past ten to 20 years. 25 Thank you. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 24 1 DR. MILLER: Well, first, there were no 2 deaths in the trials. So, number one, that's the only 3 death that we had in a human volunteer in over 100 4 years, and that's the truth. 5 Number two, I can't comment on the adverse 6 events other than the fact that the significance of how 7 you define a adverse event is very difficult for 8 different people. Did we underreport? Perhaps we did. 9 I don't know that. I was not in charge. 10 Third, we did not delay information from 11 anyone other than at the wishes of the family. And I 12 can assure you that the family wanted no information. 13 And I feel our responsibility was to the family and not 14 to the Baltimore Sun. 15 The last point is, we did not lie about 16 anything and I would like you to show me where we lied. 17 Lastly, I take full responsibility for this as the 18 head of the institution. 19 CHAIRPERSON MARSHALL: Thank you, Ed. Greg. 20 DR. KOSKI: A clarifying remark in this 21 discussion around adverse events versus serious 22 unanticipated events. The reporting that's required or 23 expected in the different types of studies that are 24 done, the clinical trial under FDA regulation versus a 25 physiologic study of the type that was being conducted PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 25 1 here are very different. 2 The expectation for sort of conducting a 3 survey of all of the adverse events in order to form a 4 profile of the expected events that might occur, the 5 frequency of those events in the context of developing 6 a new drug is a situation where basically you have to 7 capture ever event no matter how minimal or how serious 8 so that one gets a full spectrum of the events. That's 9 a very different set of expectations than in a 10 physiologic study where one is looking to see where 11 there is just a serious unanticipated event that 12 actually results in harm or the potential for harm 13 either to one of the participants as a subject or even 14 one of the investigators. 15 In most of the studies of the type that Dr. 16 Miller has described, the events are in general 17 reported locally and dealt with locally and relatively 18 few of those have been reported or even need to be 19 reported to the Office for Human Research Protections. 20 That's the nature of the distributed system under 21 which we've operated. That doesn't mean that there 22 isn't real room for improvement of this system and 23 certainly greater clarity because if an investigator is 24 involved in two types of research, it ultimately leads 25 to confusion as to what should be reported to whom. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 26 1 And certainly we saw this in the wake of some of the 2 gene transfer studies after the death of Jesse 3 Gelsinger. 4 So this is an area that certainly I think Dr. 5 Miller and Adil have drawn attention to. It's an area 6 that our office is actively working on and it's one of 7 those -- I think one of the great challenges that we 8 have to address and we look forward to continuing to 9 work with both of you in that. 10 CHAIRPERSON MARSHALL: I have Jonathan and 11 then Judy, and then Mark, and then I'd like the open 12 the floor up to our public members. 13 DR. MORENO: After these last remarks that 14 Greg made and Dr. Miller made, both go to the concern 15 that I had, namely, how do we ramp up the system for 16 getting this information available and probably even 17 more complicated than that, sort of just from a logical 18 point of view is, how do we tell what's relevant to the 19 drug or substance and what isn't? And that's partly, I 20 guess, a problem of helping investigators, once a 21 consensus has been reached about the criteria to know 22 what those criteria are. So it's a pretty complicated 23 business. 24 CHAIRPERSON MARSHALL: Judy. 25 DR. SIEGEL: Thank you for your remarks. My PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 27 1 question actually goes to training of clinical 2 investigators which I think -- my background is from 3 the pharmaceutical side, so you can put my comments 4 into perspective. But you mentioned that it problem is 5 the pharmaceutical industry that should seriously 6 consider putting some more money into training. And 7 while I don't disagree, I think many of the issues that 8 we've seen have actually been from non-industry- 9 sponsored trials. NIH-sponsored trials, other 10 sponsored trials. And so I would like to say that 11 probably this is more a joint responsibility. 12 I think as far as when you're doing -- at 13 least FDA-sponsored trials the reporting requirements, 14 the oversight requirements are actually much greater 15 than non-FDA-sponsored trials and therefore a lot of 16 the education is sort of on the ground education as you 17 see what's going on at a site. So I think I would sort 18 of put into the mix that if we're going to have 19 education then it probably should be from two sources 20 at least. 21 DR. MILLER: No, I totally agree. I was just 22 thinking that that pharmaceutical houses have -- since 23 they're changing so dramatically now, they're going to 24 have to figure out how to get this thing done and done 25 right. And I totally agree, there's multiple sources PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 28 1 of funding for it. 2 CHAIRPERSON MARSHALL: Mark and Alan and then 3 we'll open it things up to the floor. 4 MR. BARNES: Hi, Dr. Miller. 5 Just a couple of brief questions. One is, 6 can you describe a little bit about the extent to which 7 you decided -- Hopkins decided to beef up the staffing 8 for the IRBs in response to this situation? 9 DR. MILLER: Sure. 10 MR. BARNES: And the other question is, if 11 you had to identify just one single reform that you 12 think is the most important reform that Hopkins 13 undertook to protect human subjects, what would that 14 be? 15 DR. MILLER: Well, I think the first answer 16 was, we looked at the entire process and in order to 17 decide what kind of infrastructure what needed to have 18 in place, and we decided we needed in areas of the 19 database that was better than the old database that we 20 had, so we totally reconfigured that. 21 Secondly, the issue about how do you get your 22 minutes transcribed more quickly? And I mean, it's 23 kind of down at that level. 24 Third, the number of IRBs became very 25 important because if you had a greater number they saw PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 29 1 less protocols, they could spend more time on the 2 protocols. We scheduled meetings every week, and we 3 made sure that we had people that were fully trained. 4 OHRP came in Saturday and Sunday. We had a 5 room full of people to continue to go over all the 6 rules and regulations, so that was another piece of 7 what went in. 8 The most important thing that we've done, I 9 would just say that we have, in a variety of forums, 10 emphasized not only that we put the infrastructure in 11 place, but that everybody in the institution knows how 12 important this is. I mean, we had town meetings, big 13 town meetings with the president of the university 14 there. And we have hit on it. I had a retreat on the 15 eastern shore, brought all my chiefs, all my hospital 16 chiefs, and Greg agreed to come and we spent a whole 17 day just on this issue. So, if you want to ask one 18 thing, I think it wasn't one thing, but a whole host of 19 things that talks about this. How can we do it better? 20 I mean, Hopkins has always been a leader, we 21 want to continue to lead. So that's where we are. 22 DR. FLEISCHMAN: As we go around nationally 23 and look at IRBs, many of the professors who sit on 24 IRBs do it out of altruistic goals. And it's very hard 25 to get people, as you well know, to sit on these PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 30 1 groups. 2 DR. MILLER: Yes. 3 DR. FLEISCHMAN: So what do you think your 4 experience teaches all of academe about how do we 5 incentivize IRB membership and work? Ought the medical 6 school be sharing some dollars with the clinical 7 departments about such people? How does the promotions 8 process take this into account? I mean, each of those 9 issues, I think, we'd benefit from your wisdom. 10 DR. MILLER: Well, first, essentially as 11 things have gotten tough in medicine over the last ten 12 years, the proverbial P&L sheet for every physician, 13 you can't have a young professor -- assistant professor 14 spending 20 to 30 percent of their time on IRB 15 activities and not figure a way to pay them. So we 16 have started that process. After, admittedly, going 17 through Ruth Vaden's group to say, now are we doing 18 something wrong here by paying, and we actually asked 19 Greg and they thought it was not a bad idea. We had 20 always paid the head of it and the vice chair of that 21 IRB for their time, but we had not done that for the 22 other people on the committee. 23 Now, we don't necessarily give them the full 24 20 or 25 percent, but we put dollars toward that. 25 Secondly, we make sure that there's PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 31 1 infrastructure in place and easy for them to do their 2 job on the IRB. So Internet technology and so forth so 3 they have access to things, able to query things. 4 And then, third, the issue of promotions. 5 Admittedly, we still have a one-track promotion system 6 at Hopkins and we probably always will. There's no way 7 to change that. We tried that, lost that one. Tried 8 that, lost that. 9 [Laughter.] 10 DR. MILLER: But we certainly put that as 11 part of the mix of why someone should get promoted at 12 the professor level at the associate professor level. 13 That's service, community service, that's a very 14 important piece of what makes Hopkins and that counts 15 toward it. And I can tell you, someone who has only 16 gotten their RO1s and hasn't done any of those other 17 things doesn't get through the promotions committee any 18 more. 19 CHAIRPERSON MARSHALL: Let me ask if there 20 are any of our ex-officio members or public members who 21 would like to ask Dr. Miller a question. 22 And if you could just please tell us who you 23 are. 24 DR. MATHER: Dr. Miller, I am Dr. John Mather 25 and I head the Office of Research Compliance and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 32 1 Assurance in the VA with a $1.4 billion portfolio and 2 as you can imagine, many, many protocols across the 3 system of some 115 VA medical centers. 4 I would like to make one comment and then ask 5 one question. I think the commentary about AEs, SAEs, 6 unsuspected and all the rest of it is an issue that 7 we're all struggling with. 8 Greg had convened a group a couple of weeks 9 ago and out of that meeting it became abundantly clear 10 that those of us that were a table from across many 11 agencies were immediately more and more concerned about 12 how this can be clarified for everybody. Because 13 within our system it's very clear, there's not point in 14 sending every unsuspected SAE to my office which is 15 basically what goes on right now. And for my office to 16 be struggling with that is an immediacy that concerns 17 me because the word needs to be out, not in my office, 18 but at a level where it matters, and that's 19 particularly in cooperative studies where it's going on 20 in several sites. And I don't think we have that right 21 yet. 22 My question is to probe with you a little bit 23 more about the issue of the training and education of 24 investigators. 25 DR. MILLER: Yes. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 33 1 DR. MATHER: We in the VA declared 18 months 2 ago that you couldn't put in a merit proposal without 3 some sort of certification that you had taken an 4 education training program. At that time somewhat 5 unspecified, but since then required that you had to 6 pass some sort of examination in the concert of 7 whatever, you know, test you take. I'm troubled that 8 we don't really have a keen sense of what are the core 9 requirements of investigators whether you're doing 10 clinical trials, whether you're doing health services 11 research, or whether you're doing all brands of 12 research and maybe on top of that what specifically 13 investigators need because they're diversifying or 14 specializing in certain tracks such as clinical trials. 15 From what I've seen, the Association of 16 Clinical Research Professionals, ACRP, is taking this 17 on as an issue mainly for the area of clinical trials 18 which is the farmer piece of it. But everybody needs 19 some sort of basically notion. 20 Do you have a feel for where the focus for 21 getting that done might need to be? I mean, is it a 22 government function? Is it a nongovernment function to 23 take that lead? Would you favor mandated education for 24 investigators in some manner or another so that it says 25 you cannot due human subjects research without having PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 34 1 this little piece of paper that says you're somehow 2 certified in that regard? 3 DR. MILLER: I think this is a very difficult 4 issue and we're struggling with it right now because I 5 don't think we want to get to the point of just having 6 a little piece of paper that kind of you got through 7 the test and you don't have any real understanding of 8 why you're moving forward. So we've been a little 9 cautious in going to that. 10 And what we've done is, we've put now 11 together a two-day course. There is a summer course 12 that also goes on. And I think we're going to move to 13 some kind of certification and I think it's going to be 14 various levels of certification. But, again, I'm 15 afraid to do that until we really pin down the most 16 important things that that investigators needs to know 17 to move forward. And I' not sure we're there yet, to 18 tell you the truth. I wish we were. But I don't think 19 we're there. There's a lot of stuff out there that we 20 haven't nailed down as to the point that my senior 21 people satisfied yet. 22 DR. MATHER: Who takes the lead? 23 DR. MILLER: And I personally think since 24 basically clinical investigation it ends up to be 25 either the subject or the volunteer at the local level, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 35 1 and the accountability has to be at the local level. 2 How you interact with OHRP and other agencies to help 3 you form that I think is something that needs to be 4 worked out. But I'm still pretty much a pragmatist and 5 say, local level is the best way to do it. 6 CHAIRPERSON MARSHALL: Elliot and then I'll 7 call on this lady. 8 DR. DORFF: Along those lines, one model that 9 you might want to think about is what happens with 10 accreditation for universities where its done not by 11 government, but it's done by the profession, as it 12 were. Because presumably the expertise in doing 13 clinical research is in the profession. But that -- I 14 mean, it does sound as if, I mean, if you have Ph.D. 15 programs in this, it does sound as if there are some 16 people around that should know how to figure out what's 17 really important. 18 DR. MILLER: And that's why we're developing. 19 I don't think many institutions don't have that 20 luxury. So -- 21 MS. BLEVINS: My name is Sue Blevins and I'm 22 with the Institute for Health Freedom. I have a 23 comment and then a question. My first comment is, I 24 want to say, Dr. Miller I worked and trained at Johns 25 Hopkins and I have great respect for the institution. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 36 1 I know how hard the doctors and nurses work there. I 2 was there way back in the 1900s -- in the 1980s and I 3 know the dedication of all the people there, and I know 4 the intent is always to heal and make patients better. 5 Having said that, I want to share this one 6 anecdote that I think is also important for the record 7 and it raises a question. Having said that I know the 8 motives are good, I know the motives are pure of the 9 doctors, the hospitals, the researchers. At the time 10 in the 1980s I was roommates with two other nurses and 11 one came home one time crying. She worked on a bone 12 marrow transplant unit. And she said, you know, 13 patients are being told what the outcomes of this 14 certain protocol is. 15 They were getting a transplant and then 16 drugs, I guess, chemotherapy, I'm not -- I worked on 17 the urology unit, I wasn't familiar with that. And she 18 said, but they're really dying from the side effects, 19 but the cancer is being cured and they're not being 20 told this. And she was very upset and thought it was 21 an ethical dilemma. 22 And, of course, she wasn't going to interfere 23 with the protocol, but that raises the question of, I 24 have always wondered, when you're counting deaths, or 25 when you're counting adverse events, you know, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 37 1 sometimes that patient is considered a cure when really 2 they're dying from the -- the drugs are causing major 3 organ failures. And I'm sure the drugs and the 4 protocols have improved over the years, no doubt about 5 it. 6 But I guess I question a little bit the, how 7 are the deaths counted? I'm not challenging your 8 honesty. I know you're being honest, but sometimes 9 there are side effects that aren't always included in 10 the protocol and how do we get that information out to 11 patients so that we can make, not only informed 12 decisions, but even better informed decisions? 13 DR. MILLER: Well, as you know, bone marrow 14 transplant, that whole history is one of the two places 15 that started it. And there is no question in the '80s 16 there were a lot of issues about complications of how 17 big the does, how high the dose. I think today we try 18 to best categorize it. But in these studies, for 19 instance, patients with multi myeloma are going to be 20 in these trials. And some who get bone marrow 21 transplants, do they die from their therapy, or do they 22 die from their progression or their disease or is there 23 a complication? 24 I don't have a good answer to that. That's 25 an individual -- I mean, how you report that out, there PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 38 1 probably needs to be more clarity. Maybe Greg wants to 2 speak to that. It's a toughy. 3 DR. KOSKI: Just quick. I think that it is 4 tough. But if one approaches it by having an 5 appropriate capture of the information in a time frame 6 where it can be put to use and have it analyzed by 7 individuals who understand the situation and can look 8 at it objectively as to reach a determination as to, 9 you know, whether or not the treatment is better than 10 the disease so to speak is probably as close as we can 11 get, I think, to the kind of approach that would serve 12 everyone's interest. 13 I mean, obviously in a clinical trial that's 14 exploring, you know, a new approach to treating a 15 disease, if one knew whether or not it was going to 16 work, whether or not it was going to be safe and 17 effective, one wouldn't be doing the study in the first 18 place. So that it has to be made clear, you know, on 19 the front end that indeed there are risks, there are 20 unknown, but then it's our responsibility to very 21 carefully watch and monitor the progress. 22 Now, how we do this, what is the appropriate 23 role of an institutional review board in that process? 24 What's the appropriate role of a medical monitor, a 25 data monitoring committee, or a data and safety PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 39 1 monitoring report? They all play a roll. And, of 2 course, this thing keeps coming up, you know, no matter 3 where we look at the discussion in human research, we 4 do have these kinds of shared goals and 5 responsibilities. 6 But this whole process of actually what's 7 happening to the progress of trial studies that are 8 under way and how we can get information in real time 9 and use it to prevent harm to individuals who are 10 actually actively enrolled in trials underway, I think 11 is one of our great challenges now and we are working 12 to address that issue. 13 DR. CHODOSH: Let me introduce myself by 14 saying that this is my 50th year after graduating from 15 Hopkins. And I -- 16 [Laughter.] 17 DR. MILLER: Now, let me see, you've given to 18 the fund already; right? 19 [Laughter.] 20 DR. MILLER: The letter is in the mail and 21 I'll be glad to send you a thank you letter too. 22 [Laughter.] 23 DR. CHODOSH: Well, I must say that when all 24 this started I was feeling a little bit abashed and 25 ashamed of that fact that I had been a graduate and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 40 1 that I am a graduate. However, I also have a long 2 experience in clinical research. And what Greg is 3 saying is very important, but also there's this other 4 aspect which we can't ignore. 5 Number one, investigators by and large are 6 not in a position to be judging whether that side 7 effect is important to that particular situation. And 8 we need to have monitoring boards. They are essential. 9 We have not had them. It is less likely to happen in 10 a non-multi-center study, but it's just as important 11 there because, if anything, you need to have 12 independent people looking at these. 13 And the FDA, although I don't agree with 14 everything they do, one thing they do, do, and that is, 15 you report all severe things. And they define them, 16 any hospitalization, any prolongation of 17 hospitalization, any of this kind of thing. Even 18 though you know deep down it has nothing to do with the 19 study, someone else has to evaluate that in a prompt 20 way. Otherwise we're kidding ourselves. 21 DR. MILLER: Now, we do have monitoring 22 boards in place at Hopkins. Just so that you do know 23 we do that independent. But, for example, in this 24 particular case, you know, that investigator made a 25 decision that that subject's cough played no role. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 41 1 That was a decision made by the investigator. 2 DR. CHODOSH: That wasn't my problem. I 3 could understand why -- I'm a pulmonologist. What I 4 didn't understand is when I heard of that death, my -- 5 said, my God, that's hexamethonium." Because I knew 6 about it and I wasn't a cardiologist. I was a 7 pulmonologist and it was well-known that this did 8 occur. 9 CHAIRPERSON MARSHALL: One last question. 10 MS. CAMP: My name is Robin Camp, just a 11 private citizen. Can you speak more specifically about 12 what the informed consent form was for the person who 13 died versus the improvements in informed consents now 14 and whether these forms are very specifically drawn or 15 they're more general in nature? 16 DR. MILLER: Well, first, they're 17 specifically drawn for each study. So that's one. 18 Secondly, in the particular consent form it 19 did not have all eight elements. It did not mention 20 the fact that the patient might die, the subject might 21 die. And also importantly, it mentioned hexamethonium 22 as a medication, giving the patient a false sense of 23 security that this was a drug. And it really no longer 24 was a drug, it was a chemical substance. 25 I think I answered all three pieces. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 42 1 MS. CAMP: But in terms of the improvements 2 now for -- 3 DR. MILLER: Oh, all the element are there. 4 They're looked at very carefully. We make sure that 5 we've got all the pieces there. And I would say 6 there's probably more discussion at the IRB about the 7 consent form then had occurred in the past. 8 MS. CAMP: Thank you. 9 DR. MILLER: Certainly a significant 10 improvement on that. 11 CHAIRPERSON MARSHALL: Ed, I want to thank 12 you so much for coming. I asked Ed just this past 13 Wednesday to come and he immediately said yes. And 14 he's given us an extra half hour of his time. 15 I guess I would like to close this session by 16 observing that I think one of the things that is 17 emerging as a theme in the current will to reform the 18 system of protecting human research subjects is the 19 fact that maybe one of the most important things that 20 we can do is to have responsibility and accountability 21 at all levels and at many levels within a research 22 organization; responsibility for protecting human 23 subjects. And the real way to make that happen is to 24 have the head of the institution be the one who sends 25 out a very clear message as to the importance of that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 43 1 and to set the institutional culture and the tone. 2 And, Ed, it sounds as though you're providing 3 that leadership and I don't think that really there's 4 anything perhaps that's more important than that. And 5 rewarding those who do well, and sanctioning those who 6 don't do well in terms of the expectations that are set 7 out. So, Ed, thank you so much for coming. We really 8 do appreciate it and it's great to see you again. 9 [Applause.] 10 CHAIRPERSON MARSHALL: We do have some 11 flexibility in our schedule. I'm not sure necessarily 12 that Mark will need all of the time that he's got 13 coming. 14 So I would like to move along to Dr. Alan 15 Fleischman. The children's workgroup has been working 16 very hard and I think perhaps doing some of the hardest 17 work that can be done. And that is really going back 18 to basics and fundamentals and looking at definitions, 19 and I think trying to provide OHRP and the research 20 community, IRB members, investigators with some 21 guidance as to interpretation of the regulations 22 governing the research with children. And also some 23 concrete examples of how protocols or individual 24 situations might fit into an interpretation of the 25 regulation and it's very clear that that is sort of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 44 1 guidance, I think is desperately wanted and needed by 2 the research community. 3 So, Alan, thank you very much for the 4 leadership you've been providing the children's working 5 group and the very hard work that has been done. 6 DR. FLEISCHMAN: Thank you, Mary Faith. And 7 let me say first of all that the children's workgroup 8 has been working extremely hard. It's easy to lead a 9 group of really competent wonderful people who are 10 interested in working hard to solve some tough issues. 11 I want to remind you that the first task of 12 the children's workgroup was to answer a question that 13 Dr. Koski had raised, and that was to look at the 14 regulatory structure for children and consult for OHRP 15 in its goal to consult for Congress about the adequacy 16 of regulation for children. 17 And I will remind you that the workgroup and 18 then NHRPAC and then OHRP did in fact suggest that the 19 regulations were sufficient, but there were issues of 20 accountability, there were issues of clarification, 21 there were issues of definition that needed work. 22 So the workgroup has begun to take those 23 issues that OHRP reported to Congress needed some 24 clarification. We report today on two of a whole host 25 of issues that we would like to attack and are PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 45 1 attacking. We are doing them systematically and 2 serially. 3 We understand that we haven't completed the 4 task. We are at the beginning and we started with 5 perhaps the two most easy and yet most controversial 6 within the children's regulations. We are attempting 7 here in our report to clarify interpretation of the 8 concepts of minimal risk and minor increase over 9 minimal risk which are basically in 46.404 and 46.406 10 in the Federal Regulations. 11 Today we report on what is a close to final 12 draft of what we would like NHRPAC's support on in 13 terms of the clarification of those two concepts. It 14 is the workgroup's hope to be able to present examples 15 in addition to these definitional issues. We have not 16 come to closure on our examples, so we decided not to 17 present them today. And the workgroup will be back 18 with examples. But we would like to come to closure on 19 the substance, if we can. 20 So let me just go through this very quickly 21 starting with minimal risk. And I think everyone has 22 in front of them the report and I hope -- do our public 23 members have copies? 24 CHAIRPERSON MARSHALL: It's available on the 25 table out front. So if you didn't pick one on the way PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 46 1 in -- pick one up, please feel free to grab yourself 2 one. 3 DR. FLEISCHMAN: So we start merely by 4 defining "minimal risk" as it is defined in the Federal 5 Regulations in the Children's regs reminding you that 6 it's probably and magnitude of harm or discomfort 7 anticipated in the research and that that is not 8 greater in and of themselves than those ordinarily 9 encountered in daily life or during the performance of 10 routing physical or psychological examinations or 11 tests. 12 We interpret the definition, "we" the 13 workgroup, of "minimal risk" to be the level of risk 14 associated with the daily activities of normal, 15 healthy, average children. Risks includes all harms, 16 discomforts, indignities, embarrassments, and potential 17 breaches of privacy and confidentiality associated with 18 the research. Conceptually this minimal risk standard 19 defines a permissible level of risk in research as the 20 socially allowable risks which parents generally permit 21 their children to be exposed to in non-research 22 situations. This is our take on clarification. 23 Now a couple of codicils. First, children of 24 different ages in their general average, normal, 25 healthy lives are exposed to different levels of risk. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 47 1 We believe that needs to be taken into account. And, 2 certain groups of children are routinely exposed to 3 greater risks as part of their daily lives because of 4 circumstances in which they live, circumstances of 5 poverty, marginalization in our society. This level of 6 increased risk ought not -- underline the word "not" -- 7 be interpreted as minimal risk just because it is part 8 of the common experience of these otherwise healthy 9 children. 10 So the standard, as we see it, is that 11 standard of the average healthy normal child within our 12 society. Now, that, of course, is going to require 13 interpretation still by local IRBs. 14 Now, we also interpret the phrase, 15 "ordinarily encountered in the daily life" or during 16 the performance of routine physical or psychological 17 examinations or tests. We believe that there is an 18 equivalence of risk standard here. That we ought not 19 only include those things that are done during a normal 20 routine physical or psychological exam. But we ought 21 to look to those things that are equivalent in risk 22 that are done with children in research. 23 And then we remind our colleagues in IRBs and 24 investigators that all participation in research is 25 voluntary and that there ought be no obligation to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 48 1 participate even when the risks are minimal, and as 2 you'll see later on, we get to our obligation to even 3 ameliorate minimal risk and make it as minimal as 4 possible. 5 Let me pause there which is a brief outline 6 of the minimal risk substantive issues and get 7 comments, questions or thoughts. Elliot. 8 DR. DORFF: My basic question is, why? Okay. 9 In other words, I'm talking about the paragraph at the 10 bottom of page one, top of page 2. If people both in 11 terms of age and in terms of the situation in which 12 they live, if children are exposed to certain kinds of 13 risks that are different from the ones that other 14 children are exposed to of different ages or different 15 social conditions, why do you say that that should not 16 be understood as minimal risk? 17 I mean, what I have in mind is in terms of 18 age. For example, if you were doing a test on, I don't 19 know, physical stamina or something on that order, I 20 mean, you would expect a teenager to have more physical 21 stamina than a six-year-old. And so shouldn't that 22 then -- shouldn't then whatever minimal risk is 23 understood to be reflect that difference? 24 And similarly in terms of if you were doing, 25 let's say, a sociological study of children who grow up PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 49 1 with alcoholic parents, now, that's clearly a higher 2 risk than -- hopefully than the norm of our society. 3 But, nevertheless, if you were to do this -- I mean, if 4 you were trying to define what minimal risk is for that 5 child, it seems to me that you really have to take that 6 into account. I'm worried about the kind of objective 7 standard that you're presuming which probably is, what 8 middle class, white America, or something like that. I 9 mean, is that -- now that's what I'm worried about. 10 DR. FLEISCHMAN: Well, the standard in 11 minimal risk we do believe is an objective standard. 12 We'll invoke the Levine approach, if the tiger is in 13 the community. I don't want to go -- I don't want to 14 tell Bob's story, but I think our workgroup believes 15 that just because children are living within less than 16 optimal environments ought not redefine what level of 17 risk is acceptable with no compensating benefit unless 18 they fit into the category of having a condition or 19 disorder which would allow them then to be the subject 20 of research that might be a minor increase over 21 minimal. 22 And I think we specifically have dealt with 23 the child of the alcoholic the child within poverty, 24 the child in less than optimal social circumstances in 25 the minor increase over minimal risk category. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 50 1 The reason we do that, is because we believe 2 that category requires more careful scrutiny to protect 3 those otherwise vulnerable subjects. 4 Now, the age issue that you raise, we do 5 believe is within minimal risk. So the enhanced 6 stamina of the adolescent would be under minimal risk 7 if that was consistent with their age appropriate 8 levels. So the only thing that we've eliminated is the 9 social circumstances. We believe age has to be 10 relative within the standard of minimal risk. 11 DR. DORFF: Then I would just suggest that 12 you separate them out in that paragraph. Because the 13 way that the paragraph reads is that the last sentence 14 refers to the two previous sentences. 15 DR. FLEISCHMAN: Okay. 16 DR. DORFF: And the two previous sentences, 17 one talks about age and one talks about social 18 circumstances. So if you understand age to be 19 different, then social circumstances you should 20 indicate that. 21 DR. FLEISCHMAN: Thank you. Abbey. 22 MS. MEYERS: I think what you're talking 23 about would address one of the questions that I wanted 24 to ask about the Johns Hopkins study on children, the 25 lead paint study which also got a lot of publicity and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 51 1 which is, don't take it for granted that because these 2 children are being raised in the slum that they're 3 going to be exposed to lead paint and therefore it's 4 all right to put them in an environment where they're 5 purposely going to be exposed to it. 6 But my question is, I read through all of 7 this. I think it's very, very good, but it's really 8 written for testing of antihistamines. It doesn't talk 9 about sick kids in here. You know, I mean, what is a 10 minor increase over minimal risk if the child has 11 cancer. One of the big problems with the whole 12 pediatric exclusivity thing is that they're studying 13 the antihistamines. But they're not studying cancer 14 drugs in children. And, so I'd like to see very sick 15 children addressed here, you know, maybe more than a 16 minimal increase in risk is worth it. 17 DR. FLEISCHMAN: Well, Abbey, we 18 wholeheartedly agree with you. And we're about to 19 embark on that if NHRPAC agrees with this beginning. I 20 mean, we've got to start somewhere. We decided not to 21 bite it all off and present you with an entire analysis 22 of all the work we plan to do. Our next approach will 23 be on the prospect of direct benefit, research 24 including questions about drug trials. We have now 25 added to our workgroup an oncologist ethicist PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 52 1 pediatrician, Rick Codish [ph] who has written 2 extensively in informed consent in clinical trials in 3 cancer, specifically to address the kinds of concerns 4 that you raise, but we're about to embark on those. 5 Placebo-controlled trials, prospective direct benefit 6 trials will be our next move into this area. But we 7 feel that unless we can come to closure on these two 8 categories, it's going to be very hard to get to 46.405 9 which is the next category. 10 Bob. 11 DR. R. LEVINE: Some of you have ample proof 12 that I'm technologically challenged. 13 DR. FLEISCHMAN: I think we all knew that 14 before today, Bob. 15 [Laughter.] 16 DR. R. LEVINE: I think this report is 17 terrific. I think that with the suggestion, the 18 addition that Elliot made and I think was accepted that 19 it will be terrific plus. 20 The only one thing that I am concerned about, 21 and this was suggested by Abbey's comment, is that it 22 clearly says that minimal risk standard is defined in 23 relation to interventions or procedures that do not 24 hold out the prospect of direct benefit. I would think 25 it would be of great help to people out there and some PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 53 1 in here if it went on to say very clearly that minimal 2 risk has nothing whatever to do with procedures that do 3 hold out the prospect of direct benefit. 4 When Abbey talks about the need to look at 5 children with cancer and evaluate treatments there, we 6 don't evaluate the treatment as to whether or not it 7 presents more or less than minor increase above minimal 8 risk, in that case the risk benefit balances between 9 the risks of the drug and the benefit in terms of 10 treatment of the trials disorder. "Minimal" does not 11 relate to that at all. And I do hope that that 12 clarification will be made prominently. 13 About my tiger story, it was a leopard. 14 [Laughter.] 15 DR. FLEISCHMAN: Sorry. 16 DR. R. LEVINE: No problem. Except that I 17 was in Africa where they have leopards, but not tigers. 18 And I was saying something that in a perhaps amusing 19 way is relevant to this discussion, and that is, I 20 visited a place where leopards and lions wandered 21 freely between people's houses. And when I got there 22 that a leopard had eaten the neighbor's dog the week 23 before. And I said, this would give special meaning to 24 contemplating what goes on in the everyday-life 25 experience of the child. And I think Alan has been PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 54 1 very careful to say, that is not what we're talking 2 about. That is not an everyday experience for the 3 average child. Thank you. 4 DR. FLEISCHMAN: Felice. 5 DR. F. LEVINE: I just wanted, as a member of 6 the working to underscore the reasoning of our working 7 in making the distinction, Elliot, to the issue that 8 you raised about social circumstances. We actually 9 struggled with it for some time, especially in the 10 context of let's say, non-intervention kinds of studies 11 where you are interviewing or perhaps observing 12 children or adolescents who are in challenging social 13 circumstances, but even there we still thought that 14 taking the additional precaution to make sure that 15 children in those circumstances weren't essentially 16 being exploited as additionally vulnerable populations 17 was a worthwhile thing to do. And that's how we sort 18 of parsed that distinction. 19 DR. FLEISCHMAN: Sandy. 20 DR. CHODOSH: I guess I still have one area 21 of concern. And, you know, everything that is written 22 here is just beautiful, except the fact that if you're 23 not going to allow research that has no benefit to the 24 individual, in this case a child, how are we going to 25 obtain information about normal children? There seems PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 55 1 to me that, you know, the base for looking at 2 abnormality is to know what "normal" is. And there's a 3 lot, as you well know, that we still do not know about 4 the differences of why children are different than us 5 big folks. 6 Is that going to be addressed? Because that 7 seems to be sort of a black hole that's developed in 8 all of this. You know, either it's not risky to the 9 individual and it's within a "normal" standard of 10 living or it's going to be a benefit and there's this 11 thing in between. 12 DR. FLEISCHMAN: Can we bracket that question 13 for a comment and I'll call on you right after we talk 14 about the minor increase over minimal risk and see if 15 we come back to that conversation. My rapid fire 16 response is that the way we've defined "condition" 17 would allow for research our normal physiology at a 18 certain level of risk would not allow research on 19 normal physiology at a higher level of risk unless 20 there was the prospect for direct benefit. And having 21 begun my career on IRBs in the '70s arguing with some 22 nephrologist about how would they ever know if they 23 didn't do and they had a whole host of things they 24 needed to do with normal children, somehow it took them 25 a little longer, but we figured it out but we would PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 56 1 never let them do it. 2 But I think there is a question when we have 3 a non-consenting patient consent through surrogacy as 4 to what level of risk we would allow. And I think 5 we'll come back to that after the minor increase, if 6 you don't mind. 7 Mark. 8 MR. BARNES: Alan, I'm sorry, I don't mean to 9 be dense, but let me ask a question I think has been 10 asked a couple of different ways again. How does this 11 standard take into account the difference in perception 12 of sort of acceptable level of daily risk by geography? 13 That is, you know, IRBs are really local decision- 14 making bodies. And when I think of the kind of people 15 who tend to sit on IRBs in New York City and they tend 16 to be, you know, pretty well-educated people who have a 17 very minimal risk standard for their children, and I 18 compare that to, for example, where I grew up in the 19 south where one-third of the adults at any one time are 20 mentally ill, one-third are alcoholic, and one-third 21 are barely functional and they -- 22 [Laughter.] 23 MR. BARNES: -- and there is a very high 24 tolerance for the fact that children beat each other 25 with sticks and bricks and things like that. And I -- PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 57 1 MS. MEYERS: I disassociate myself with that 2 remark. 3 [Laughter.] 4 MR. BARNES: And I do wonder about the, you 5 know, the perceptions of risk really do markedly differ 6 between, you know, rural areas versus urban areas, even 7 if you -- even leaving aside, you know, the 8 socioeconomic factor and just looking at geography. 9 And so I guess my question is, do you see this -- does 10 the working group see this as a national standard or 11 does it really allow for local variations? 12 DR. FLEISCHMAN: I think the whole process of 13 IRB review allows for local variation, but it is a 14 national standard in the sense that what we are trying 15 to do is objectify this standard, look at it in a way 16 that suggests that there is a limit on what we will 17 allow for children in this category. And I too wish to 18 be disassociated with your comment as a New Yorker who 19 would be thought to have those thoughts. 20 [Laughter.] 21 DR. FLEISCHMAN: I want to be, you know, I 22 want to be sure -- 23 MR. BARNES: I can say it, you can't. 24 DR. FLEISCHMAN: Absolutely. 25 [Laughter.] PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 58 1 DR. FLEISCHMAN: But I do think that it is 2 important and Elliot raised it right at the beginning 3 that we do consider the socially compromised children 4 as unduly vulnerable and we do have to think about 5 protections at the IRB level, that there have been some 6 untoward events that are in the history of research 7 ethics, and I think we need to think carefully about 8 how IRBs relate to that group. I mean, that's our 9 working group's standard. 10 I'll go back to Felice. 11 DR. F. LEVINE: In that context I think, 12 Mark, your underlying point is also a very good one and 13 it will take some degree of education, I think, of IRBs 14 nationally and maybe all of us as well as locally to 15 also not stereotype the notion of a normal healthy 16 child as someone who also doesn't exist. I mean, that 17 all of this texture is part of the range of what is in 18 the normal healthy zone and that it's not some, you 19 know, white, ineffective person who doesn't hustle and 20 tussle in the way that children and youth do. And 21 we'll need a much more variegated understanding of what 22 childhood and adolescence is like so that we know what 23 normal and healthy is. 24 DR. FLEISCHMAN: Greg and then Bob and I 25 would invite our public commentators to come to the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 59 1 microphones now for just on the minimal risk question. 2 DR. KOSKI: One just quick comment on the 3 notion of locality of IRB decision-making. While 4 everyone agrees that there's a critical importance to 5 being aware of local situations and all of that, we've 6 also seen examples of what I call regional disparities 7 in IRB decision-making that are sometimes like medical 8 decision-making, it's not really based on rational. 9 And to the extent that total, you know, local reference 10 points could result in some IRBs allowing research that 11 would basically be considered unethical in other parts 12 of the country represents a range of non-uniformity, 13 perhaps, that I think probably exceeds what may be in 14 the best interests of research subjects, whether they 15 be children or adults. 16 And so this notion that you know, every local 17 IRB should be given complete autonomy to reach whatever 18 decision they want to is one that I think we have to 19 give some further thought to. 20 DR. FLEISCHMAN: Bob. 21 DR. R. LEVINE: Thank you. I want to 22 underscore the importance of what Sandy said and add 23 one thing to it. 24 First, ever since the children's regs were 25 published in '83, we have had this problem on getting PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 60 1 normal control data for procedures that presented minor 2 increase over minimal risk, and it's a persistent 3 problem. And I hope -- I wish you well in dealing with 4 it. But the other problem that's very important is 5 that it really -- if you read the regulations, 6 literally, which is perhaps the only way you can read 7 words, it says you can't do phase one oncology in 8 children. 9 Now, what we've done is shuffled around that 10 by saying it's become fashionable to call it phase 11 one/two. But I hope you address that most thorny issue 12 very carefully. 13 Going back to the minor increase and normal 14 volunteer, child volunteer, I also hope you'll throw in 15 real cases like OHRP's reaction to the NICHD's protocol 16 where they use siblings of children with a condition. 17 That seemed to attract severe criticism while only 18 about five or six years earlier virtually the same case 19 was published in the IRB journal as a celebration of 20 how to solve the thorny problem. So there's mixed 21 messages out there. 22 Thank you. 23 DR. FLEISCHMAN: Susan. And then we're going 24 to go on, if I don't see anybody at the microphones 25 we're going to go on to our second part which is the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 61 1 minor increase over minimal risk. 2 MS. KORNETSKY: Yes, I'll just make a final 3 comment sort of about the variability and some of the 4 issues that have been raised. Having working with an 5 IRB for the last 18 years with this definition, I think 6 part of the problem is that there are still IRBs and 7 many IRBs will use a relative standard or an absolute 8 standard. So I think there still always will be some 9 variability, buy this will at least be a national way 10 that we can begin to bring things a little bit closer. 11 So I think this will do a lot more than you think for 12 those institutions that review IRBs for children. 13 DR. FLEISCHMAN: Thank you. Would you 14 identify yourself, please. 15 MR. DOYLE: Yes, I'm Bill Doyle from 16 Pittsburgh. In Pittsburgh we are born and bred. We 17 don't leave, we stay. The local IRBs only have, 18 usually, a flavor of Pittsburgh. I think by making a 19 national standard or applying that we are going to take 20 away some of the autonomy. Because that's all we know 21 is Pittsburgh. We don't know New York. We don't know 22 the south that you were talking about. We know our 23 neighborhood, and we know what kind of risk that we're 24 going to expose our kids to. We shoot BB guns at each 25 other as long as we're wearing leather jackets nad PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 62 1 goggles. 2 I'm concerned about -- they use paint balls 3 now, but I'm concerned about this idea that we don't 4 have a local flavor and that we want to make a national 5 standard. I agree that minimal risk should be an 6 absolute definition within constraints. But the local 7 flavor is very, very important. 8 DR. FLEISCHMAN: Thank you. Yes. 9 MR. SCHATZ: My name is Gerald Schatz and I'm 10 a budding bioethicist and a reformed lawyer. I am a 11 former member of the NICHD IRB. I am not familiar with 12 the sibling study. But there are a few things I 13 learned on the NICHD IRB. Having represented abused 14 and neglected children in the District of Columbia, I 15 was especially interested in the approach of social 16 intervention experiments. I am delighted to see in 17 this Fleischman paper the reference to unwanted 18 disclosures. 19 And I think it will be very helpful if we 20 observe the spirit of it which is that simply that a 21 child lives at a higher degree of risk daily does not 22 mean that we can further expose that child to higher 23 risks. And here I would urge that we not 24 compartmentalize our thinking, and this subgroup has 25 not. And that's when we see people living at a higher PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 63 1 degree of risks daily, we consider them as more 2 vulnerable. 3 DR. FLEISCHMAN: Thank you. 4 Let me go on to the second part of the report 5 and that will bring these two together, I think, and 6 Sandy will have the first comment after the second 7 presentation. 8 In 46.406, research involving greater than 9 minimal risk and no prospect of direct benefit is 10 permitted if it is likely to yield generalizable 11 knowledge about the subject's disorder or condition. 12 And I'll remind you that there are some 13 predicates here. The risk must represent a minor 14 increase over minimal. The intervention or procedure 15 presents experiences to subjects that are reasonably 16 commensurate with those inherent in their actual or 17 expected medical, dental, psychological, social or 18 educational situations. That the intervention or 19 procedure is likely to yield generalizable knowledge 20 about that disorder or condition. And that that 21 generalizable knowledge reaches a very high standard, 22 that is, a vital importance standard for understanding 23 or ameliorating the subjects' disorder and that 24 adequate provisions are made for soliciting assent and 25 permission as is part of the regulations. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 64 1 We put into this report a little bit of 2 history here only because we wanted to highlight that 3 all the way back -- all the way back -- at the National 4 Commission -- 5 [Laughter.] 6 DR. FLEISCHMAN: -- in the early -- no, at 7 the National Commission, the report research involving 8 children and these -- this concept was integrated into 9 the final federal regulations precisely because of the 10 problem that's been raised about how would we be able 11 to find out important things about children in order to 12 be able to enhance taking care of children, 13 understanding children, bringing therapeutic 14 interventions to children. 15 So this area was created to allow research a 16 vital importance that would not otherwise be 17 permissible based in the minimal risk standard. These 18 regulations impose a significant limit on the 19 discretion of parents to permit participation of their 20 children, but at the same time do allow some research 21 that entails more than minimal risk without the 22 prospect of direct benefit. 23 I have to say in looking back at those 24 discussions, having not participated in those 25 discussions at that time, I think it was really a very PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 65 1 thoughtful way to deal with this very difficult issue. 2 So we have embraced this concept. We remind 3 in that second paragraph on page three that while the 4 definition of minimal risk is indexed to the risks 5 encountered in the daily lives of normal, healthy, 6 average children, the minor increase over minimal risk 7 is not an absolute standard, that the permissible level 8 of risk associated with a minor increase over minimal 9 risk should be just a bit more than the level of 10 minimal risk, and that's an important concept. 11 You know, we've thought about drawing a 12 continuum scale with minimal risk over here and 13 significant risk over here, and a minor increase over 14 minimal risk, not on my nose, but close to my left 15 hand. And I think that we see it that way in the 16 workgroup and that it is an important concept so that 17 it's just a bit more than minimal, it must be 18 commensurate with experience or with expected 19 experience, that both has something to do with the 20 level of risk, but not absolutely to do with the level 21 of risk because some of these children are going to 22 have experiences of very significant risk which would 23 not be consistent with this standard. But it has to at 24 least be within their commensurability so that there 25 might be some concept of consent or assent based either PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 66 1 in experience or in expected experience. 2 And, thirdly, that the significance of this 3 research much yield generalizable knowledge of vital 4 importance. Now, I haven't met a researcher that 5 doesn't think that their research will realize 6 generalizable knowledge of vital importance. But I 7 have met an IRB that's questioned it. 8 So I do think that we must ask the 9 investigators to make that case and the IRB must review 10 that case. It isn't going to be hard for them to make 11 the case, but it will be important for IRBs to review 12 the case. And it's two issues, both generalizable 13 knowledge and vital importance. And generalizable 14 knowledge speaks to the validity of the study, the 15 biostatistical and approach to the study and the 16 research design of the study. If you can't answer a 17 question, then you ought not be doing the study and 18 then it has to be of importance to the -- and even 19 vital importance to the subjects. 20 Do you want to just break in there? 21 DR. R. LEVINE: [Off mic.] 22 DR. FLEISCHMAN: Okay. Now, we did bite off 23 the question of disorder and condition and perhaps this 24 is the most controversial part of this report, we think 25 it's critically important. We've spent a good deal of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 67 1 time thinking about it to speak to the question that 2 Sandy raised, and that is, what constitutes a disorder 3 or condition within these regulations for which the 4 minor increase over minimal risk standard would then be 5 applicable. 6 And we have argued that the phrase "disorder 7 or condition" refers to a characteristic of the group 8 of potential research subjects and implies that this 9 characteristic can be understood more broadly than 10 simply a specific disease or diagnostic category. 11 We interpret the concept of disorder or 12 condition as relating to a specific characteristic 13 which describes a group of children, a physical or 14 social condition affecting children or the risk of 15 certain children developing a disease in the future 16 based on diagnostic testing or physical examination. 17 Thus, for example, and this is just examples, 18 thus for example, prematurity, infancy, adolescence, 19 poverty, living in a compromised physical environment, 20 institutionalization, or having a genetic 21 predisposition to future illness are some of the 22 disorders or conditions of children that can, under 23 appropriate circumstances based on IRB review warrant 24 permissible research that presents levels of risk that 25 are a minor increase over minimal without the prospect PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 68 1 of direct benefit. 2 So that's on the table for conversation. And 3 I've got Sandy first, then Bob, then Mark, and Adil. 4 DR. CHODOSH: I'm still not sure that the 5 black hole has been filled and that we're still talking 6 about a minor degree over minimal risk and there are 7 lots of situations where that would be exceeded and 8 there would be no benefit to the individual and perhaps 9 benefit to the generalizable knowledge. Okay. 10 And I think that it depends on how you tie 11 those things together that if we don't have an avenue 12 or a pathway to lead to generalizable -- important 13 generalizable knowledge that exceeds the bit more than 14 minimal risk that we are not going to ever achieve what 15 we need to do with children. I'm not a pediatrician 16 but I know that as a clinician for many years, one of 17 the big problems is that you didn't know how to treat 18 children with drugs. Okay. Because they were never 19 tested in children. 20 And those were, of course, sick situations. 21 But how do you establish general, good physiologic 22 business when it does go a bit more than minimal risk 23 and there is no benefit? And so I don't see that this 24 hole has been filled. I think there is still going to 25 be a problem for IRBs. I think there is still going to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 69 1 be a problem for science. 2 DR. FLEISCHMAN: Well, Sandy, I think the 3 pediatric research community has sometimes voiced those 4 concerns. The regulations gave us the 407 section. 5 The 407 section was in fact to deal with those kinds of 6 very important vital research studies that could not 7 fit into a minor increase over minimal risk, did not 8 have the prospect for direct benefit, but could be 9 elevated to the level of the Secretary for review. 10 Now, you will remember that before recent 11 history, before the last couple of years, and we could 12 argue why it's increased in the last couple of years, 13 but before the last couple of years there were really 14 very few research projects of that level that came to 15 the Secretary's attention. In fact, two. 16 Now, there is perhaps a broader number now 17 and it may -- some of us think it may be to do with 18 IRBs that are a bit more paranoid about making some of 19 these judgments in an atmosphere of concern about 20 compliance, et cetera, and lack of clarification of 21 some of these definitions. But the 407 committee still 22 sit there ready, I am told, to deal with these issues 23 and that would be where the issues of concern that 24 you're raising would be placed. I mean, in the 25 regulatory structure that's -- it's not a total black PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 70 1 hole, there is the possibility of that. And I mean, 2 that's where it sits right now. We will get to the 407 3 questions ultimately with our workgroup, although there 4 has been some good work, I think, already promulgated 5 on the 407 side. 6 Bob, and then Mark, and then Adil. 7 DR. R. LEVINE: I just want to add a bit of 8 an extension to something Alan has already said, and 9 that is, what is the purpose of the commensurability 10 standard? I feel confident I can talk about that 11 because being much older than Alan, I was part of the 12 process that developed it and he would have been 13 invited if he was my age. 14 [Laughter.] 15 DR. R. LEVINE: The purpose of 16 commensurability standard is not to say, well, the kid 17 is going to have ten bone marrows anyhow, another two 18 or three don't make any difference. That's not what it 19 is meant to say. What is it meant to say is that 20 children who have had a bone marrow examination or who 21 are in a setting where they can expect to have one 22 will, by virtue of their much greater familiarity with 23 the procedure, know exactly what it is or what it's not 24 that they are agreeing to have. They'll know how much 25 it hurts and so on. So it's exclusively to reinforce PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 71 1 the power of the assent or what the Commission also 2 called "knowledgeable agreement." Thank you. 3 DR. FLEISCHMAN: Thank you, Bob. 4 Mark. 5 MR. BARNES: Yes, thank you. Alan, there's 6 something that has always troubled me about the 7 standard that we did before with the minimal risk 8 versus the increase and it's actually just brought into 9 sharper focus by the working group's interpretation of 10 the minimal risk standard as really being a kind of 11 national standard. And that is that if you accept your 12 -- and I think it's wise, I don't have a quarrel with 13 it, if you accept your national standard for minimal 14 risk as being the ordinary average healthy child, I've 15 always been troubled by the criterion B which the 16 intervention or procedure presents experiences to 17 subjects that are reasonably commensurate with those 18 inherent in the actual expected medical, dental, 19 psychological, social or educational situations which 20 actually allows you to import all of their 21 socioeconomic variables in making it sort of a -- 22 almost a class-specific inquiry as to whether the 23 experiences of this particular enhanced risk, this risk 24 over minimal risk would really be how it will be 25 gauged. It will be measured by their actual lives PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 72 1 rather than by a national standard. 2 And, I mean, it's always troubled me, but it 3 particularly troubles me given the -- I think -- 4 appropriate interpretation that the subgroup -- that 5 the working group has given to the minimal risk 6 standard. And I wonder if you guys thought about that 7 or talked about it? 8 DR. FLEISCHMAN: Uh-huh. 9 MR. BARNES: And the sort of the larger 10 question is really, is the purpose of the working group 11 to kind of adumbrate or kind of do an exegesis of the 12 existing rule, or is the -- sorry. 13 DR. FLEISCHMAN: I'm going to go to my lawyer 14 over here to find out what he means. 15 [Laughter.] 16 MR. BARNES: -- or is the purpose really to 17 say that the regulations themselves, you know, may 18 actually be inappropriate and need to be -- that the 19 text itself needs to be worked over rather than just 20 putting a gloss on the existing text. 21 DR. FLEISCHMAN: We think -- I mean, the 22 workgroup has thought a good deal about this and 23 believes that the regulations actually both were 24 intended to support this kind of work based in the 25 history of the conversations that the Commission and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 73 1 that the federal regulations have. And we embrace that 2 argument. 3 We do believe that it's important to look at 4 children who are in uncertain circumstances who are 5 marginalized, who are socially impacted upon by their 6 environments. And to study how one might help those 7 children to learn more about children of alcoholic 8 families or children in poverty, or children in lead 9 toxic environments is an important part of pediatric 10 research. We think the regulations intended that. 11 What we are trying to do is to clarify that 12 in the sense to say that those are conditions worthy of 13 research. We put it into this category rather than 14 into minimal risk. We think it's safer for the IRB to 15 be more wary of that. These are youngsters who could 16 be coerced into research or could be more likely to 17 have things done to them or for them that we ought to 18 at least scrutinize carefully. And that, in a sense, 19 argues that the IRB, you know, in this categorization 20 in 406 rather than 404, really has to take that more 21 carefully into consideration. 22 It doesn't mean you can't do the research, it 23 means that you have a very -- a bit of a higher 24 standard, higher scrutiny, this generalizable knowledge 25 of vital importance. It, for me as an IRB member, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 74 1 pumps it up a little bit in terms of what we're asking 2 of the researchers and what we're asking of our own 3 review. I mean, that's where -- that's how I've seen 4 it right from the beginning. 5 And let me comment to Robert that I didn't 6 have the pleasure of being on it, but I did testify. 7 So I was old enough to do that. 8 MR. BARNES: Could I just follow-up quickly? 9 Is that okay? 10 DR. FLEISCHMAN: Yes. 11 MR. BARNES: I mean, but I'm not quarrelling 12 with the idea that you would define the disorder or 13 condition as including -- that the definition of 14 disorder or condition in criterion C is really about 15 what you would study. And I'm not quarrelling with the 16 idea of condition as broadly defined. What I'm 17 quarrelling with and what's always troubled me is 18 criterion B which allows you -- which seems to me to 19 actually relax the standard. In other words, for the 20 minimal risk what you guys have said, I think 21 appropriately, again, is that there is a national 22 standard for minimal risk and that's appropriate. 23 CHAIRPERSON MARSHALL: And socially 24 allowable. I mean, and that's a concept that we wanted 25 to get at this problem. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 75 1 MR. BARNES: Yes. But then in the allowable 2 risk under 406, it seems to me the criterion B is 3 actually saying that you are allowed to take into 4 account the fact that this particular child may come 5 from a riskier environment and therefore you can you a 6 lower risk standard. That's my problem. 7 DR. FLEISCHMAN: Well, we're trying to 8 separate out that commensurability standard and maybe 9 we haven't done it well enough in that second paragraph 10 on three. What we are saying is the commensurability 11 standard does speak to assent and permission because 12 both parents and the child will have some understanding 13 of what it means that particular research intervention 14 or procedure, it does relate to the little bit more 15 than minimal, but it doesn't allow for those increased 16 risks that would be more than a little bit over 17 minimal. 18 Now, perhaps we can say that better in that 19 paragraph, but that's our intent. And I think it 20 speaks to some of the issue that you're raising. I 21 don't know if it speaks to all of it. 22 I've got Adil, then Judy, and then Abbey, and 23 then Bob. 24 DR. SHAMOO: Thank you. I think Mark 25 introduced my concerns very well in a much more fancier PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 76 1 language, thank God. 2 [Laughter.] 3 DR. SHAMOO: The problem still the issue 4 brought up under the minimal risk problem potentially 5 exploiting children is the same under this category. 6 And the one concerning me the most is the word "or 7 condition." "Disorder" I can understand, "or 8 condition." "Condition" as the dictionary defines is 9 state of being. It could be anything, height, place 10 they work, age, gender, broken leg, social conditions, 11 poverty like you said, even race to be very honest, a 12 state of being. It can be used as an excuse to exploit 13 children in any kind of research. Literally there is 14 an elephant. 15 The intent of the National Commission was 16 really first to close this loophole, period. It was a 17 member of this panel here since he is older than all of 18 us -- he's the one who opened the door for -- 19 rightfully -- for some kind of other research into this 20 category. But the intent of the National Commission 21 was that window of opportunity was small, not as large 22 as it's been. 23 For example, being a sibling of an 24 incarcerated individual, a healthy child, just because 25 he has a brother, a child, in prison, that should not PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 77 1 make him a human subject volunteer on these kind of 2 definition of a condition. And that's what is 3 happening. This thing has been interpreted very 4 broadly. Let me read to you what the National 5 Commission said which you quoted, which is nice, but 6 you quoted the soft part of what the Commission said. 7 The Commission said, "research with children, 8 to the extent that it involves any exposure to 9 otherwise non-existent risks raises a serious ethical 10 question and calls for particular ethical 11 justification." Furthermore, Kenneth Ryan, the 12 Chairman of the Commission, after he heard all the 13 argument and the discussion, he said, let me make it 14 very clear and he reiterated his own understanding. He 15 said, and I quote, "The Commission's intention in 16 46.406 is to permit the conduct of research intended to 17 develop important knowledge of disease state from which 18 certain children suffer and for which they are the only 19 appropriate subjects." 20 And I'm saying is, your definitions here of 21 "condition" or the way you have placed it, I could pass 22 any, any social, behavioral characteristics to allow 23 children to be exploited in this kind of research. And 24 the sibling issue in fenfluramine is a good example of 25 how that definition is being used and this definition PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 78 1 will not excluded the fenfluramine experiment. 2 DR. FLEISCHMAN: I think that our workgroup 3 would go a step further than Dr. Ryan in that quote. 4 Our workgroup would argue that condition is a 5 characteristic of a group of children that warrants 6 examination. Our workgroup would lean on the Belmont 7 report and its argument of beneficence obligations to 8 enhance the health of children through careful analysis 9 of the disorders and conditions that children suffer 10 from. 11 So I think that we do have a difference in 12 interpretation here. We do think our workgroup does 13 think that it is consistent with the regulations. It 14 does not require rewriting of the regulations, and that 15 it is defensible. 16 DR. SHAMOO: I think the word "condition" 17 should be narrowly defined than you have. The way you 18 have it now will allow literally -- will eliminate 19 literally almost none of the research which is 20 objectionable which is social and behavioral issues or 21 poverty or whatever it is you want to put in this large 22 tent. We will allow that kind of -- and of the word 23 condition of that particular group. Because you got 24 away from the "disorder" it's "condition" and that 25 condition is broadly defined as you have it in your PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 79 1 paper. 2 DR. FLEISCHMAN: So I think, Adil, you and I 3 may agree on what specific research projects should or 4 should not be approved. What we are trying to do here 5 is to give IRBs some clarification. We may have done 6 it inadequately. But you and I, I think, would agree 7 that there's some research that has been done, some 8 research that has been proposed that ought not be under 9 this category. But what you're asking is for the 10 definitions to be more constrained so that there would 11 be less flexibility at the local IRB level. The 12 workgroup has not come down on that side of the 13 analysis. 14 Judy. 15 DR. SIEGEL: I think my comments actually 16 relate to, Alan, just to what you're saying. On the B 17 item commensurate with actually not having been around 18 at all, Bob -- 19 [Laughter.] 20 DR. SIEGEL: Not for age reasons. 21 DR. FLEISCHMAN: Right. Judy was an 22 adolescent enrolled in studies. 23 DR. SIEGEL: Most probably. 24 I thought that your explanation of what the 25 National Commission had in mind of what commensurate PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 80 1 was actually to imply which was that the children and 2 parents involved would understand what was coming and 3 could give better assent. I think that's what's 4 missing. I mean, if a clarification of that point 5 could be put right in there about what commensurate 6 actually means. Because it actually explained it to me 7 better because actually what that says is, you don't 8 want to do something to somebody that they've never had 9 done to them before because you don't think that maybe 10 they can give good assent in that. So I think that 11 would be a good point of clarification. 12 And, also, I think that Adil's point about 13 where do the boundaries around the conditions and what 14 conditions would actually be applicable for research 15 purposes, it's the next thing of vital importance. I 16 think some guidance to local IRBs about what justifies 17 research of vital importance because I, to my mind, 18 don't know how you do that. And, so, again, you could 19 argue that if we could give some sort of discussion 20 even on what vital importance might mean, it might help 21 a local IBR decide whether some research on a condition 22 actually meets those criteria. 23 DR. FLEISCHMAN: Thank you. Madam, 24 Chairperson, I understand we have a change in the 25 agenda that we need to deal with. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 81 1 CHAIRPERSON MARSHALL: We do have a change in 2 the agenda. So just let me -- I'll outline the next 45 3 minutes or so for you. We're going to give Greg Koski 4 some time now to talk about classified research because 5 he does have to leave for a bit. So we will have Greg 6 from 10:15 to 10:30. We will break at 10:30 for 15 7 minutes, resume at 10:45 and the proceed on until 8 11:30. 9 Thanks, Greg. 10 DR. KOSKI: Mary Faith, thank you very much 11 for the flexibility and my apologies to everyone that I 12 do have to flip my schedule around a bit today. But we 13 did at least want to give you a brief update on the 14 events that are underway in follow-up, in fact, to the 15 discussion that we had before this committee back at 16 the January meeting when we discussed the certain 17 events around bioterrorism, the impact that that has 18 had on the climate in which research is conducted. And 19 I believe Jonathan Moreno who pointed out that in these 20 times, as well as in others, there is an appropriate 21 place for classified research done appropriately. But 22 that there are certainly special challenges that are 23 raised by conducting research in the classified domain 24 and that those challenges deal particularly with the 25 protections for the subjects of that research. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 82 1 Now, much of our discussion in January went 2 back to the report from the President's advisory 3 committee on human radiation experiments where indeed 4 it became knowledge that classified research had been 5 conducted on individuals sometimes without their 6 informed consent, sometimes without appropriate 7 reporting and so on. And that was one of the bases for 8 the recommendations issued by that advisory committee 9 that included not only mechanisms for improving the 10 sort of reporting and tracking, recordkeeping around 11 classified research so that people are aware of what's 12 going on and there are some appropriate accountability 13 and oversight brought to that, but also recommendations 14 for amendments to the Common Rule, the regulatory 15 structure to ensure that when such research is proposed 16 that it is both appropriately reviewed and that due 17 consideration is given to the protection of human 18 subjects. 19 The types -- actually, I believe there's 20 information in the books and perhaps available out 21 front for others that have to do with the specific 22 wording of the recommended language for the amendments 23 to the Common Rule. But the requirements included such 24 things as ensuring that there was a lay individual who 25 had appropriate security clearance who was required to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 83 1 be present at the time of review. And that there be 2 appropriate mechanism for appealing the decision of a 3 committee. And in the case that the individual who was 4 bringing an outside consciousness to that group 5 concerns about the research as to whether or not it 6 should go forward on that right of appeal would be made 7 to the White House to the President. 8 Now, I'm not going to review all of the 9 provisions there because we have done that and so it's 10 written. But in response one of the many parts of the 11 response of the then Clinton administration to the EG 12 report was an executive directive that called upon the 13 federal agencies that operate under the Common Rule to 14 adopt the proposed amendments and actually to do so on 15 an accelerated timeframe. 16 All of the agencies save, I believe two, 17 perhaps three, in fact did put their signature to that 18 within the appropriate time frame, but it never quite 19 got to completion. And so in the context of today's 20 circumstances we are revisiting that recommendation. 21 We basically have discussed the issue before the human 22 subjects research subcommittee of the committee on 23 science. 24 We have asked the federal agencies to once 25 again review these recommendations within their PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 84 1 agencies and to make some determination as to whether 2 or not the positions that they would adopt today are 3 the same or different from the provisions that they 4 have taken previously. Whether there might be 5 additional changes that might be required within any 6 proposed amendments to the Common Rule, or whether what 7 had been previously proposed might go forward. 8 Now, the recommendation actually, as it 9 ultimately went forward was in the form of what was 10 called an "interim final rule" which would mean that 11 once it is put out there, although there would be a 12 period for public comment, it becomes effective 13 immediately and that's done in order to bring the 14 immediacy of the protections to bear. 15 So at the present time we are actively 16 engaged in this process indeed at the HSRS meeting 17 which is coming up next Wednesday. We will be 18 discussing this once again and already many of the 19 agencies are actively engaged in the process of taking 20 it through their own houses to see where they stand. 21 So that, Madam Chairman is the current status. 22 CHAIRPERSON MARSHALL: Greg, we do have -- we 23 are actually ahead -- some time for questions from the 24 committee or our ex officio or public members. 25 Jonathan, I see your hand is up. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 85 1 DR. MORENO: First of all, I want to thank 2 Greg and the other members of the HSRS for picking up 3 what I think is really an important issue because I'm 4 persuaded, as I said before, that there will be the 5 political will for classified research on human 6 subjects in the future. Although we're told that's not 7 the case now. And we don't want to make our generation 8 responsible for the mistakes of previous generations 9 and to repeat those mistakes. 10 The language it seems to me in the interim 11 final rule is pretty good. I only want to say at this 12 point that I think this group will, once the rule is 13 finalized, want to look at the following problem. 14 The problem is one that has been encountered 15 in the past for 40 or 50 years in this area. Namely, 16 what counts as research with respect to national 17 security issues. If -- and I can give you chapter and 18 verse of the way that this problem has unfolded over 19 the years, but to take a couple of examples, the 20 400,000 plus men who were deployed in the nuclear test 21 shots in the late '40s through the early '60s were not 22 considered to be human subjects. And, yet, in many 23 cases they were given radiation badges, their blood and 24 urine was tested, and so forth. 25 Only in two kinds of activities, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 86 1 psychological panic studies and flash blindness studies 2 were they considered to be part of human experiments. 3 So everything turns really in this area on the question 4 of what counts as an experiment or what counts as 5 research. So which box bureaucratically that gets put 6 in is absolutely critical. 7 CHAIRPERSON MARSHALL: Thank you, Jonathan. 8 I have Judy and then Bob. No, I'm sorry. 9 Okay. Bob. 10 DR. R. LEVINE: Once again, what did the 11 National Commission do about this. The National 12 Commission had extensive hearings on research that was 13 conducted by what was called the intelligence 14 community. And one of the problems that seemed not 15 susceptible to resolution was that if and when they 16 would establish IRBs, they would have required that 17 every member of the IRB, including the community 18 representatives would have to have the appropriate 19 level of security clearance. 20 This, even in the 1970s, was somewhat alien 21 to the idea of having what since has been called 22 "transparency" applied to the deliberations. It 23 strikes me that that might be an intractable problem 24 because you don't want people without security 25 clearance getting access to things that have security PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 87 1 clearance for some good reason. 2 The other thing that Jonathan suggested is 3 the issue of what counts as research. In the last ten 4 years, when I've seen various specialties wonder about 5 how they're going to make careful determinations of 6 whether what they're doing or which of their activities 7 count as research, I've become increasingly impressed 8 that there's an awful lot of stuff on the -- an awful 9 lot of stuff that various agencies and disciplines 10 engage in that the definitions don't work very well. 11 I was chair of the CDC committee and we 12 looked at such things as outbreak investigation, 13 routine surveillance, case studies, in case of 14 something outlandish happening. And many of these 15 exercises use all of the devices that researchers 16 commonly use. More recently I've seen the same thing 17 in health policy research where some, but not all of it 18 is exempted from coverage. And in -- what's it called 19 -- quality improvement activities in the health care 20 setting. 21 I'm beginning to think more and more that we 22 should not be working with the definition of research 23 trying to gerrymander it so that it fits here, but not 24 there and so on. But to do what the health policy or 25 the public health policy, what was done on behalf of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 88 1 this group, and that is to create some well-circumcised 2 -- 3 [Laughter.] 4 DR. R. LEVINE: Sorry about it. Well- 5 circumscribed exemptions to coverage from -- not from 6 all the regulations. I think exemptions in coverage by 7 all the regulations is a mistake. But to exempt 8 certain sorts of things from some aspects of the 9 regulations that are pretty onerous. And I hope we 10 have a chance to worry about that later. Thank you. 11 CHAIRPERSON MARSHALL: Abbey and then I'd 12 like to open the -- we have about two minutes. So, 13 Abbey, and then anyone, ex officio. 14 MS. MEYERS: I would just worry about 15 exempting this kind of research from anything. Because 16 if experiments can be done on soldiers who are more or 17 less like prisoners, I mean, they have no choice if 18 they're in the military but to obey orders and 19 participate in an experiment. So I really would want 20 those guarantees of human protections to be even 21 stronger in the case of defense. 22 DR. MORENO: Again, this misses the point. 23 The problem is that whenever there's been an issue like 24 this, Abbey, it's simply been defined as not an 25 experiment but as part of training for some potential PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 89 1 combat situation. So the overreaching problem is what, 2 as Bob said, what do we put within that framework -- 3 what do the powers that be at the time put within that 4 framework. 5 CHAIRPERSON MARSHALL: We have time on the 6 agenda later, I would like to just get to the folks who 7 are standing in line here. John. 8 DR. MATHER: Dr. John Mather with the VA. I 9 want to identify myself clearly with Jonathan Moreno's 10 remarks. I think this issue is a very serious one 11 about what constitutes the scope of research that is 12 classified research and how it might or might not 13 differ from our classic definitions, Bob Levine, that 14 appear in the Common Rule. 15 We have seen survey research done which 16 doesn't theoretically, you know, hurt anybody, but 17 clearly does, by the very nature of the questions. So 18 it doesn't just have to do with radiation exposure and 19 those kinds of things. So I think we need to think 20 very seriously and carefully about what is classified 21 research. 22 Greg mentioned the human subjects research 23 subcommittee which has been reengaged with this issue 24 over the past couple of meetings. And there's a very 25 clear impetus to get this done and done quickly. And I PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 90 1 think we need to move it along and move it along with 2 haste, but not to the point that haste makes waste. 3 I think this issue of security clearance has 4 come up. Clearly those agencies that have an 5 intramural program, they will have to make sure that 6 IRBs as per CIA and so forth appropriate security 7 clearances and I don't think that's inappropriate in a 8 broad national sense. There are other agencies like 9 the VA that probably will be really challenged on that 10 issue because IRBs are down at the VA medical center 11 level. 12 So if there's any kind of research that's 13 done in a classified nature, it's not exactly clear how 14 that will play out. One may have to do it depending on 15 the particular site and it may just be that, you know, 16 the chair of the IRB there will be the person that 17 would have to get security clearance. 18 So it does raise some other issues for those 19 of us that don't have naturally intramural IRBs that 20 run the full gamut, maybe like Polly is going to 21 mention about DOD and agencies like that. 22 CHAIRPERSON MARSHALL: We have about three 23 minutes, but I do want to observe that we can continue, 24 I think, part of this discussion tomorrow afternoon or 25 tomorrow morning at 10:30. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 91 1 So, Greg has to walk out the door in about 2 three minutes. 3 MS. BLEVINS: Sue Blevins, Institute for 4 Health Freedom. My question is, how do you reconcile 5 informed consent with classified research? And is 6 there an assumption here that if it's classified 7 research that the individuals receiving the treatment 8 or intervention are not giving written informed 9 consent? Because if they are, they could be sharing 10 with family members. 11 I would also make a recommendation that if 12 there isn't an IRB or somebody overseeing the research 13 that perhaps whoever is involved in the treatment at 14 least one person out of that group would also be 15 receiving the treatment or intervention. Just a 16 recommendation. 17 DR. KOSKI: The recommendations do not 18 basically allow for a waiver of informed consent in 19 these kinds of situations except under those conditions 20 where it might otherwise be waived under the 21 regulations so that indeed the presumption would be 22 that for any research that involved greater than -- 23 that it would clearly carry with it the requirement for 24 informed consent. And that poses special challenges as 25 we've already heard from Jon and others in a situation PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 92 1 where the individuals who participate may in fact have 2 to have security clearance in order to go ahead 3 But there are a number of logistical issues 4 that have to be considered here and quite frankly I 5 think that even if one moves ahead expeditiously to put 6 forth the rules there is still going to be a need for 7 extensive guidance and further work on how the rules 8 would actually be applied. 9 CHAIRPERSON MARSHALL: Thank you. Please 10 just let us know who you are. 11 MS. BOLL: Hi, I'm Patty Boll, I'm with the 12 Department of Defense and I would like to make a couple 13 of comments on what was spoken here. In reverse order, 14 we do -- we have covered subjects and their legal 15 access to classified information. And all of our 16 subjects do have to have the appropriate clearances so 17 they are given truly informed consent. They are given 18 all the information they need because they have the 19 right tickets and the right access to have that 20 information. So because of that they are bound by the 21 same security constraints as a soldier would for a 22 classified mission. They can't talk about this with 23 family, but we give them enough access to resources to 24 discuss the risks. They can still talk to physicians, 25 to lawyers, to things like that as to what's going on PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 93 1 so that we make sure they can truly give informed, 2 voluntary consent. 3 And on the lines of voluntary consent, in our 4 DOD directive we have special clauses for the 5 protection of military subjects. When you are asking 6 military to participate as volunteers, we make sure 7 that the chain of command is not part of that process. 8 So soldiers, sailors, marines, flyers have the ability 9 to truly decline participation and their chain of 10 command is not part of recruitment. And we are very 11 specific that that cannot happen and under certain 12 situations when you are trying to recruit groups of 13 people, we make sure that there is an ombudsman as part 14 of that process to ensure it is fair and there is no 15 coercion. 16 We are still grappling with how do we define 17 research versus training and under what scenario are 18 you looking at this question? Is it research, is it 19 training? Because you're right, when it is training, 20 your unit goes. That's what you volunteered to do when 21 you raised your right hand and joined the military. 22 But we do want to make sure that we are not 23 misclassifying an activity as training when it is in 24 fact research. 25 CHAIRPERSON MARSHALL: Thank you very much. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 94 1 Greg, thank you. I know you've got to run. 2 As Greg is walking out the door, I just want 3 to make the observation before break that there is an 4 interesting appendix to the book, "The Nazi Doctors and 5 the Nuremberg Code" by George Annes and Michael Groden 6 that actually is comprised of documents that have been 7 declassified that describe the protections process in 8 some of the formerly classified research that the 9 government has entered into. And so I would commend 10 that to you as an interesting resource and then also, 11 of course Jonathan's book on "Secret State 12 Experiments." 13 So let us break then and come back at quarter 14 till the hour. 15 [Brief recess taken at 10:35 am.] 16 CHAIRPERSON MARSHALL: Time to resume. If 17 committee members could take their seats, please. 18 We are just going to start. If those of you 19 who are in the room could please take your seats. We 20 will turn the discussion back over to Alan. 21 DR. FLEISCHMAN: Refocusing on the children's 22 report, we have Abbey, Bob, and Jonathan, if he comes 23 back on the list. And then Felice. Felice is back. 24 Good. Abbey. 25 MS. MEYERS: I absolutely agree with what PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 95 1 you've written on disorder and condition. And I have 2 to tell you that in the Orphan Drug Act we've used the 3 same terminology about disorder and condition. The 4 reason is, a disorder is something like a syndrome or a 5 disease. But a condition can be caused by an accident 6 or trauma or anything. A broken leg is not a disease, 7 it's a disorder. So you have to differentiate between 8 the two. 9 And I wanted to know if what you've written, 10 from what I've seen here, if it -- how it would address 11 something like taking a spinal tap on a person with 12 Down's syndrome? Because, in my mind, I would not 13 allow a spinal tap on somebody with Down's syndrome 14 based on what you've written. 15 DR. FLEISCHMAN: Well, Abbey, the devil is in 16 the details. So we would need to understand the 17 context of the research, what the question is, whether 18 that child with Down's syndrome might also have 19 leukemia. And having had experience with spinal taps, 20 and having dealt with them reasonably which some Down 21 syndrome children can, the age of the child. I mean, 22 there would be a whole host of questions. 23 MS. MEYERS: But it's more than minimal risk, 24 isn't it, for anybody? 25 DR. FLEISCHMAN: Well, our table that's PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 96 1 evolving would agree that a spinal tap for children is 2 more than minimal risk. 3 MS. MEYERS: Sure. 4 DR. FLEISCHMAN: I'm not going to talk about 5 incapacitated adults at this moment. 6 MS. MEYERS: Right. 7 DR. FLEISCHMAN: But for children -- 8 MS. MEYERS: Or for any child. 9 DR. FLEISCHMAN: -- we would agree, I think, 10 the workgroup, that a spinal tap is more than minimal 11 risk. There may be some circumstances, however, in 12 which it fits into a minor increment over minimal risk. 13 And those circumstances have to do with the 14 commensurability standard. So, for instance, just to 15 give you an example, if there were a child with 16 leukemia who had had a couple of spinal taps in the 17 evaluation, and two or three spinal taps in the 18 continuing assessment of the child's wellness, and 19 there were a protocol which required another spinal tap 20 only for research purposes and not for clinical 21 purposes, it is possible that that spinal tap could be 22 consistent with a minor increase over minimal risk with 23 appropriate permission and assent if we met all the 24 other criteria. 25 So we are not precluding that potential. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 97 1 I am going to skip to Mary Kay because she 2 has that concerned look on her face that we need to 3 deal with. 4 DR. PELIAS: My furrowed brow. I know. Why 5 did you bring -- I'm asking Abbey this, why bring in 6 the child with Down syndrome? What was the purpose of 7 that? 8 MS. MEYERS: Because of the stipulation that 9 the research could be done, the child will not benefit 10 from it, but more can be learned about their disease or 11 condition, you see. So it seems to me that a minor 12 incremental increase in risk to learn more about Down 13 syndrome from which the child will not benefit, you 14 know, how does this address that? 15 DR. FLEISCHMAN: I think the commensurability 16 standard might argue that a child with Down syndrome 17 could not have a spinal tap as a minor increase over 18 minimal risk unless that child also had had other 19 circumstances or characteristics. And we would not 20 learn about the spinal fluids of children with Down 21 syndrome potentially. And that might be a bad thing 22 that we didn't learn about it, but we wouldn't be able 23 to based on our concern about that level of risk for 24 that group of subjects. 25 We also have this concept of amelioration and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 98 1 let me take a moment to just go through those two last 2 paragraphs. The workgroup feels very strongly it is 3 the obligation of investigators and IRBs to decrease 4 the level of risk at whatever level it begins. And 5 that includes using appropriate people to do 6 procedures, that is to say, people who have experience 7 with children, and who are competent to do the kinds of 8 tests and procedures that are used in children. Also, 9 to try to teach children about the particular 10 procedures and to try to ameliorate risks through 11 education of children, through having environments that 12 are child friendly and comfortable. 13 So, theoretically, one could give an 14 argument, and I'm not about to give it here, but one 15 could give an argument that in our Down syndrome 16 program we have relationships with children in our 17 program with their parents and with their loved ones, 18 and dah-dah-dah-dah-dee, and with people who they know 19 and love where we might be able to do something more in 20 the minor increase over minimal risk than in somebody 21 else's Down syndrome study. And we would make that 22 case. I don't think it would rise to the level of a 23 spinal tap. But we could make that case that our 24 relationship with those children in our very special 25 program which involves them and does various things for PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 99 1 them and with them might create an environment which 2 might allow for certain things to be done in that 3 program that could not be done in somebody else's 4 program. 5 And that's where we argue that some levels of 6 research, thus, in this last paragraph, even in 7 research studies that have risks deemed minimal or a 8 minor increase over minimal, every attempt should be 9 made to minimize the risks and some places might be 10 able to have a higher level of risk because they've 11 done things to minimize that level that wouldn't be 12 acceptable in other places. So that we've tried to 13 deal with it there. 14 And, again, with the Pittsburgh argument that 15 local IRBs really are important in making some of these 16 judgments understanding the environments in which 17 children will have research performed, and those 18 environments do allow for local IRBs to make differing 19 assessments. 20 Bob, or Susan, are you right on point there? 21 Susan, on that point? May I, Bob? Thank you. 22 MS. KORNETSKY: Yes, I just want to comment 23 on this because I think this is very important and 24 having thought a lot about this and taking sort of 25 responsibility for this part in this document is that I PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 100 1 think it's important that you have to take into context 2 the location where things are being done, who is doing 3 it, and that that can minimize the risks, even 4 sometimes to the extent of making something minimal 5 risk. 6 And I think that what has happened previously 7 is that people look at procedures and is it minimal 8 risk or is it not? I believe that there may be some 9 procedure that in an academic medical institution may 10 be considered minimal risk and may be outside in a 11 general pediatrician's office isn't. So that has to 12 really be brought into context here. 13 DR. FLEISCHMAN: I've got Bob, Jonathan, 14 Felice, and Margaret. 15 DR. R. LEVINE: Thank you. When I raised my 16 hand quite some time ago I wanted to respond to 17 something Mark had said. He suggested that the idea of 18 commensurability removed the uniformity of the 19 protection for children, that it took away the idea 20 that there was an objective standard. There still is 21 an objective standard. The standard is minimal risk, 22 minor increase above minimal risk. 23 What the commensurability does is specify 24 which children are to be considered legitimate 25 candidates for a certain minor increase. So if the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 101 1 child has leukemia, it might be a bone marrow 2 aspiration. If the child has meningitis, it might be a 3 spinal tap. But the fact remains that it's only a 4 minor increase of minimal risk that applies to all 5 children in the U.S. who have a disease, condition, or 6 disorder. 7 Another point I wanted to make is in response 8 to what Judith brought up. She wanted to see a 9 specification of vital importance. And I am, I 10 believe, that it's going to be -- it would not be a 11 good idea to get too specific about that. I expect 12 we'll see some of this come out in the case studies 13 that Alan and his group are going to prepare for us. 14 But whenever you start specifying these general 15 categories, they lose their flexibility and it's like I 16 hear many people say, well, we ought to specify what is 17 meant by "reasonable." It's terms like this that are 18 meant to have sort of an elastic definition and I see 19 the philosopher nodding. 20 If you specify exact definitions for them, 21 you have to invent another term that will allow you to 22 describe what you want to. 23 The National Commission chose not to specify 24 this and it chose not to specify many other terms. One 25 of the concerns I have is that in public policy we PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 102 1 frequently specify or stipulate definitions for terms 2 that have separate meanings or different meanings in 3 the common usage. I lobbied against use of the term 4 "minimal" to describe minimal risk. Because people who 5 weren't in on the conversation might look at the 6 dictionary and find that it means "least possible." 7 And so now when we hear about cutting back the risks 8 even in minimal risk studies unless you're in on this 9 special conversation, you might think that that's a 10 very zany conversation. Thank you. 11 DR. FLEISCHMAN: We need to shut off that 12 microphone, if you would. And then we'll go to 13 Jonathan. 14 DR. MORENO: Bob has already said much of 15 what I wanted to say. We'll find this again tomorrow 16 with the report of the workgroup on decisional 17 incapacity. And it was a sort of a flag that I wanted 18 to raise last time, namely that we need to be careful 19 since were are all policy wonks by virtue of the fact 20 that we're sitting around this table not to think that 21 a document can capture every case. 22 I think we can all agree, probably, on 23 certain cases, specific cases if we were to work as a 24 sort of a de facto IRB around this table, but no 25 regulation and no set of terms is going to capture PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 103 1 every possible case in advance. 2 I think we need to, as a group, start 3 thinking about these matters something like the way the 4 IOM has proposed, namely that this language, this 5 guidance, the regs, the IRBs, conflict of interest 6 committees, et cetera, et cetera, are all part of a big 7 human research protections program. And so there 8 should be multiple opportunities to catch bad cases 9 that concern us. And this will only be one of those 10 filters. 11 That's not an excuse not to bang away at this 12 language, or at the language of the decisional capacity 13 workgroup report or others. But there's a point at 14 which we can sit around and bring up every possible 15 nightmarish example and we'll undermine our confidence 16 that we can get the system to be better, which I think 17 we can. 18 DR. FLEISCHMAN: Thank you, Jonathan. 19 Felice. 20 DR. F. LEVINE: I think that Bob and Jonathan 21 covered what I was going to say from the vantage of our 22 working group, and let me just emphasize that in our 23 effort to think through where the bar was that the word 24 "vital importance" had meaning. That it -- that there 25 needed to be a relationship between the condition and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 104 1 the inquiry in a way where at least a PI going before 2 an IRB would not just be able to say some throw away, 3 this is important, but that's vital too, was an 4 adjective that really was saying, you know, this is an 5 important part this has to be a piece of research that 6 really made meaningful minor increment over minimal 7 risk kind of input. 8 DR. FLEISCHMAN: Thank you. Margaret. 9 MS. BORWHAT: I just have concern about the 10 last paragraph, but I understand what you're saying 11 about making sure that professionals that are skilled 12 with the children are able to minimize risks where in 13 other environments they're aren't and that we would 14 rely to a good extent on the IRB. But I am concerned 15 that the local IRB would be able to as objectively as 16 necessary be able to say, you know, our staff isn't as 17 skilled as needed for this particular study. And so, 18 you know, I think it could be enhanced with either more 19 examples or in your case studies to really try and 20 pinpoint perhaps the academic medical center where lots 21 of this type of research is done as opposed to solely 22 relying on an IRB that has an inherent interest in this 23 research being put forth in their institution and in 24 supporting their own researchers. 25 DR. FLEISCHMAN: Thank you. As some of you PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 105 1 will recall, the working group in its early comments 2 actually had great concerns about IRBs in general 3 settings have sufficient pediatric expertise. And 4 we've shared that with OHRP and feel very strongly 5 about the need for IRBs that are reviewing research 6 relative to children to have appropriate members, with 7 an "s" that have some knowledge and expertise in 8 children as well as community representation that it in 9 some sense represents the interests of children. Now, 10 most of us represent the interest of children being 11 parents or having been children. Right. I knew Mark 12 was going to do that. 13 [Laughter.] 14 DR. FLEISCHMAN: Some of us still are 15 children. Right. Okay. 16 [Laughter.] 17 DR. FLEISCHMAN: But I do think that it is 18 important to make the case, Margaret that you're making 19 and we'll see if we can add that. 20 Adil and then Elliot and then Mark. 21 DR. SHAMOO: Having several members of this 22 committee voice the opinion that they don't want to be 23 specific because policy wonks shouldn't do that because 24 we have to leave the interpretation. The counter 25 argument to that, I mean, I agree with you PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 106 1 philosophically. 2 DR. MORENO: For the record, that wasn't my 3 argument. That wasn't what I said. 4 DR. SHAMOO: All right. Go ahead and state 5 it again so -- 6 DR. MORENO: What I said was, that as policy 7 wonks we tend to over read and over write. We have 8 this fantasy that somehow a priori the document can 9 correct and avoid all the problems in the real world in 10 advance. And what I'm saying is that we need to avoid 11 that delusion. 12 DR. SHAMOO: Okay. Having reheard it all 13 over again, I still say from comments that somehow we 14 don't want to -- we don't need to be specific or -- and 15 if that is true, why are we here? The reason we are 16 here because the current regs were not sufficient, 17 there were problems. Otherwise, we won't be here. 18 There has been scandals, there has been shutdowns. And 19 more importantly all the time I bring this -- I know 20 it's like a broken record, we want to depend -- Susan 21 is laughing already because she knows what I'm going to 22 say. We bring all that responsibility to the local IRB 23 as if the local IRB is such an objective, independent 24 body to deliberate. 25 Well, guess what, they are employees, paid PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 107 1 monthly or biweekly salaries from the research 2 institution. There is only one out of 20 or 15 members 3 who are from the community also chosen. So I am 4 telling you, rely on some of the IRB alone without 5 having some specific directions to them in the language 6 leaves the problem all over again where we were several 7 years ago. So we have to be some specific. And we 8 have to reform the IRB system also itself. 9 DR. MORENO: Just again, Adil, as you know, I 10 wasn't saying we shouldn't be specific. I want to say 11 that specifically. 12 [Laughter.] 13 DR. FLEISCHMAN: Let's go on to Elliot and 14 then Mark and Susan. Susan on point. 15 MS. KORNETSKY: I just want to respond to 16 Adil. I the think having thought about these 17 guidelines and these clarifications, this is a lot -- 18 being a lot more specific than what is thought about in 19 the community right now for review in pediatric 20 regulations. So I don't think that, I mean, I think we 21 have tried to sort of have a medium where we haven't 22 defined everything, but even with my own IRB in looking 23 at this, many IRBs really like a total rubber band 24 approach this may not totally permit that. This gives 25 guidance and concrete ways to think about these things. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 108 1 So I don't think this does nothing. 2 DR. FLEISCHMAN: Bob on point. 3 DR. SHAMOO: I never said "nothing". 4 DR. R. LEVINE: Very quickly, I never said, 5 don't get specific. I just called attention to the 6 peril of stipulating definitions for words in common 7 usage. People might actually think you're speaking 8 English. 9 [Laughter.] 10 DR. FLEISCHMAN: The theologian and 11 philosopher, Elliot, would you like to -- 12 [Laughter.] 13 DR. DORFF: Along those lines, I actually 14 have two questions. One is the word "vital" which in 15 common English means, I think, a considerably stronger 16 criterion than I would imagine goes on in the research 17 community. Because if you really restricted research 18 to only that which is literally vital, you would do 19 maybe 2 percent of what you're doing now. And I mean, 20 if I were really to hold you to a standard of vital. 21 So I mean, I think one of the things you may want to 22 talk about is, you know, is what exactly does that 23 mean? 24 I mean, I assumed that it meant, and it 25 probably would have been better to have said it this PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 109 1 way is that it has a substantial promise of 2 ameliorating some disease or disorder or condition. 3 And that it's not just simply going fishing or 4 something like that. Right? I mean, that there is a 5 serious purpose to it and that there is some 6 reasonable, to use another word, a reasonable hope that 7 using the -- going through this research will lead to 8 some kind of cure or some kind of at least amelioration 9 of the condition. So, I mean, I think maybe you may 10 want to define vital in that sort of a way. Because 11 it's frankly much too strong a term for what I think 12 you have in mind. 13 The second point that I wanted to ask was 14 really along the lines that Susan was just talking 15 about. Since I really don't know this area well, how 16 do you understand the status of this document? In 17 other words, are you now summarizing more or less what 18 good research on children is all about and is already 19 happening? Or are you -- or is this a prescriptive 20 document? In other words, is this a document that will 21 -- that you intend to use to actually change the way 22 that research is being done in children? 23 DR. FLEISCHMAN: May I do a brief answer to 24 that? 25 Our understanding as a workgroup is that we PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 110 1 bring to NHRPAC our wisdom and deliberations and in 2 about three minutes I'm going to give to the 3 Chairperson a recommendation that NHRPAC approve the 4 work of working group in order to move it closer toward 5 getting to OHRP which is where NHRPAC does its work as 6 I understand it, in recommending to OHRP. And what we 7 said at the very outset of our report, it is our hope 8 -- it is our hope that this report will result in 9 creating an informative guidance to IRBs around the 10 country, and that guidance could be used by IRBs in 11 order to justify the work that they do and to 12 understand better the work that they do. And as Susan 13 has said, I think it would be of some benefit if they 14 had such documents just to go to the vital question. 15 And I think I'm convinced now that we need to speak to 16 that. 17 I'll try to draft something that's consistent 18 with this substantial promise idea. Understanding the 19 importance of serendipity, understanding the importance 20 of investigator-generator research at the NIH level 21 that has resulted in things that people never expected, 22 but in this particular case in which children have no 23 prospect of direct benefit from the work, I think that 24 the substantial promise idea is a reasonable idea. But 25 it is, you know, it's a difficult point. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 111 1 Robert. 2 DR. RICH: Simply to that point also, I agree 3 completely with Elliot that the word "vital" is an 4 inappropriate use of the term. In fact, I would submit 5 that IRBs are generally speaking, unable to judge how 6 vital. I think IRBs are well-qualified generally to 7 judge whether research is valid, perhaps even whether 8 it substantially holds substantial promise. I think to 9 really judge that a research is vital assumes a level 10 of professional expertise in a very specific area that 11 IRBs generally don't have. So I think it would 12 actually put a burden on an IRB that it's not prepared 13 to accept. 14 DR. FLEISCHMAN: We go back to Mark. 15 MR. BARNES: Just a couple of things. One is 16 that I take Bob Levine's point about the commensurate 17 standard. And from the discussion I basically divined 18 that the group seems to think that there are two 19 meanings or two purposes in standard B about the 20 commensurability. One is that one would look at the 21 situation of the child and his or her parents in terms 22 of understanding what the content of the informed 23 consent process ought to be so that you understand 24 their condition, generally speaking, in order to give 25 them adequate informed consent. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 112 1 And then the second thing would be, as Bob 2 Levine was saying that one would look at 3 commensurability in terms of the -- that one would look 4 at the risks, the inherent risks for the condition of 5 the child that was actually being studied rather than 6 the general kind of socioeconomic condition of the 7 child. 8 So those are the two things that I have heard 9 commensurability mean and if that is what the working 10 group understands, or whether it's even not what the 11 working group understands, I would suggest that there 12 really be, you know, in the next iteration of the 13 document that there really be a greater delineation of 14 actually what that is. And certainly a definition that 15 what standard B is not meant to say is that there is 16 basically a sliding scale with greater risk allowed for 17 children who are from riskier environments, which I 18 think everyone agrees that that's not what standard B 19 is meant to be. That's not what standard B is meant to 20 be or meant to mean. 21 And my suggestion really is that that could 22 be clearer in the document. 23 With that said, what I would also say to you 24 and the working group is thank you for all the meetings 25 and the efforts and everything else that you've had. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 113 1 And I know that you spent a lot of time, personal time, 2 Alan, you know, drafting these pages in previous 3 iterations and certainly the group owes you a debt of 4 gratitude for that. 5 And what I would propose is that with all of 6 the comments taken into account that we really approve, 7 you know, what's happened and what you've done and the 8 work that the working group has done and that you have 9 the blessing of the committee, as it were, to go ahead 10 to the next step. 11 DR. FLEISCHMAN: Madam Chairperson, Mr. 12 Barnes has made a motion, I think. 13 [Laughter.] 14 DR. FLEISCHMAN: But we are going to continue 15 with Susan and Sandy. Susan. Sandy. 16 DR. CHODOSH: I just want to reiterate just a 17 little bit about the vital business. And that is that 18 the assumption is that science progresses by leaps, in 19 truth it progresses by crawls. And the crawls are, as 20 has been pointed out I think appropriately, not always 21 self evident when they're being done. So that the 22 emphasis and, Bob, I think brings this out, the science 23 has got to be good. If the science isn't any good, 24 then none of this stuff should be going on, it's 25 unethical. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 114 1 And the other implication was that -- an IRB 2 had the ability to judge what would be vital. Well, 3 the truth of the matter is that they could judge that. 4 I would say the research shouldn't be done because you 5 already know the answer. You know, if it's that 6 obvious that it's going to be a very important thing, 7 you probably don't even need to do it. So that, you 8 know, the research means that you don't know the 9 answer. And if you do know the answer, you shouldn't 10 be doing that. 11 DR. FLEISCHMAN: Sandy, let me understand 12 that a little better. Because I think my concept of 13 "vital" is that it is important to the subject's 14 disorder, disease, or condition to study this issue. 15 You may not know the question. The question is 16 important. You may not know the answer at all. But it 17 is very important to look at this question within this 18 group of children. 19 And, in fact, we may not get the answer in 20 this study, but we're going to move closer to it. I 21 mean, that's where I'm looking at. And the promise of 22 amelioration argument may be even too distal. That at 23 least it moves in the direction of finding significant 24 information which may move us toward an intervention 25 which will result in amelioration, you know, that kind PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 115 1 of language is where I'm willing to say that's vital to 2 children with various levels of characteristics. 3 DR. CHODOSH: I guess you said importance and 4 brought that in and importance makes more sense, in a 5 way, than vital, that's all. 6 DR. FLEISCHMAN: Jonathan. 7 DR. MORENO: I have to say that when I read 8 that phrase in context, I read vital importance, not in 9 the abstract, but in the context of the phrase, vital 10 for the understanding or amelioration. So I read it as 11 a necessary condition for understanding or 12 ameliorating. But not that it in itself would help us 13 -- would get us to a full understanding or fully 14 ameliorate the subject's disorder or condition. 15 DR. FLEISCHMAN: Last comment, Bob, and then 16 we are going to move to Felice for a few minutes. 17 DR. FLEISCHMAN: I don't think using the term 18 "necessary condition" we're reaching the goal. It's 19 going to work here if we really take "necessary" apart. 20 What they're talking about is that you can make a good 21 case that you're pointed in the direction of 22 accomplishing something very important or at least 23 important, substantially important. That the thing you 24 are trying to accomplish is relevant to the disease or 25 condition that your subject pool has and that you have PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 116 1 to acknowledge that there are quite a few false starts. 2 Anybody who gets a vitally important result 3 every time he or she does research is probably a data 4 faker. 5 DR. FLEISCHMAN: Felice speaking to the 6 issues, the general issues now of social and behavioral 7 within the context of children; is that where we're 8 going? 9 CHAIRPERSON MARSHALL: Yes. Yes. And then 10 bearing in mind that Mark Barnes has the floor at 11:30 11 -- 11:35. 12 DR. F. LEVINE: He'll probably have it 13 faster. 14 This was really in a way looking ahead to 15 some of the other activities of what might be the 16 children's working group on the children's working 17 group agenda of which there are many both internal 18 issues relating to the specialized subparts dealing 19 with children that cross over to other working groups 20 consent may be perhaps the most obvious of them. 21 In the social and behavioral science working 22 group we've been, of course, addressing issues that 23 also intersect with childhood and adolescents in 24 particular. And I must say my own experiences on both 25 working groups really see the benefits of the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 117 1 connection and that a lot of what we were doing with 2 risk and harm I think very supportively fit into the 3 discussions of the children's working group and in 4 particular our discussions about amelioration. 5 So I'm hoping that with some of the other 6 topics that are of importance in the context that's 7 studying orphan conditions, orphan with nonintervention 8 kinds of research, that the synergies between our 9 working group and the children's working group will be 10 equally beneficial. 11 I think some of the key issues, some of which 12 also had consent that we're both hoping to address and 13 feed into the conversation and in part through me 14 within the children's working group is the issue with 15 respect to the wide variation and the definition of 16 "emancipated minors." And there's a lot of variation 17 between and among states on that and that is an issue 18 that we need in a way or NHRPAC in a way needs to 19 engage in and on issues with respect to children. 20 Also, the topic of children primarily 21 adolescents who are functioning as adults, the most 22 obvious case, for example, being adolescent parents, 23 not just female adolescent parents, but male adolescent 24 parents and the relationship between that and consent 25 and assent in particular. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 118 1 Certificates of confidentiality, when the 2 interests of the children, minor children are not 3 necessarily compatible with the issues of parents and 4 how can we reflect on what a certificate would look 5 like that could take ito account what might be not 6 necessarily complimentary interest, but competing 7 interests. Also, the whole area which I guess in part 8 links to that, the waiver of parental permission. You 9 know, we talk about the most obvious case, let's say 10 studies of runaway kids. 11 So that, you know, we have in much of our 12 conversations sort of an assumption that the research 13 is place-based often in a clinical environment or a 14 medical environment. And thus there's a parent, an 15 identified parent, an identified child that's on the 16 same page and that often the nature of the kind of work 17 in social and behavioral contexts are not necessarily 18 intervention kinds of studies and also studies where 19 there is not necessarily a known or identified parent 20 and yet it's a condition. But recognize also that 21 that's why in the children's working group we moved it 22 to the status of minor increment over minimal because 23 one should not be facile in assuming that therefore you 24 don't really have to look very long and hard about 25 those issues. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 119 1 And then I think one of the challenges, 2 especially when we're working out of health-related 3 contexts is that the primary context for research 4 outside of the health-related context is the 5 educational context, not just educational research, but 6 research in educational settings. Because that is a 7 primary site where there are inquiries of large, 8 certainly at both national and local levels, non- 9 trivial access to large numbers of children. Which I 10 think raises a generic issue that I think in part lands 11 with the children's working group and in part relates 12 to all of NHRPAC and that is that there are contexts in 13 which there are parallel pieces of either legislation, 14 in the case of the two pending bills that have now, 15 Congresswoman DeGette and Senator Kennedy. But over 16 time there have also been any number of other instances 17 where pieces of legislation or parts of pieces of 18 legislation speak to issues of concern to NHRPAC. The 19 one that I most want to make mention of with respect to 20 children's research has had a long and up and down 21 history. 22 But in the Elementary and Secondary Education 23 Act passed in January there has been essentially a 24 delegation to state and local communities, the decision 25 with respect to how -- not to IRBs, but to state and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 120 1 local communities, the decision as to how best to 2 obtain consent and written consent. And I am concerned 3 in the context of the children's working group between 4 decisions that could occur in that context outside of 5 what is the human subjects protection system and the 6 IRB role in that system. Most particularly, for 7 example, the New Jersey piece of legislation that 8 delegated this to -- or actually the New Jersey 9 legislation that actually requires written consent in 10 all school-based research, all school-based research, 11 not just educational research, but any research that 12 otherwise occurs in schools that has led at least one 13 university, understandably so, Princeton University to 14 issue a statement to its faculty that it must in all 15 work that it now pursues include written consent as the 16 sole mechanism. 17 Now, I raise this generically because, of 18 course, the current procedures have a much more 19 nuanced, I mean, we can raise this in the context of 20 the consent working group -- a much more nuanced 21 understanding that consent is a process and that that 22 process certainly takes account of the importance of 23 written consent, but doesn't have that as the sole and 24 only mechanism. And how we reconcile some of our 25 discussions in the working group around that issue and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 121 1 other subjects with other kinds of parallel activities 2 that may constrain our capacity to enhance the system I 3 think is a challenge. And one particularly on -- of 4 relevance to research on children and youth, I think, 5 just because of the saliency of that arena. And so I 6 welcome both continuing the children's working group 7 and the crossovers between these issues that come to us 8 in other contexts. 9 DR. FLEISCHMAN: Adil. 10 DR. SHAMOO: Since you mentioned the runaway 11 kid, I want to ask an example of what could be 12 quote/unquote condition to qualify those children for 13 research? A sibling of a runaway child under your 14 definition, with spinal tap to measure neurotransmitter 15 levels in those siblings who are children in order to 16 investigate is there something in biochemistry of the 17 brain that makes them runaway, these are healthy 18 siblings, will that qualify quote/unquote as a 19 condition to allow that kind of research to go forward? 20 DR. F. LEVINE: Sounds like, when did you 21 stop beating your mother-in-law. You know, we have on 22 our working table many complex cases. I must say, this 23 would be a challenge. 24 DR. FLEISCHMAN: Can I deal straight with 25 that? No. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 122 1 DR. SHAMOO: Good. 2 DR. FLEISCHMAN: In fact, the spinal tap on 3 those runaway children -- a spinal tap on those runaway 4 children would be hard for me to conceive of where we 5 would go with that today. 6 DR. SHAMOO: How about ten samples of blood? 7 Because that's exactly what happened before. 8 DR. FLEISCHMAN: Adil, now we have an 9 important -- now we have an important discussion if we 10 were an IRB. Now we have an important discussion as to 11 the environment in which it's done, the process, 12 whether it's an indwelling catheter or it's ten sticks, 13 what the experience is of the environment, what, if 14 anything, is going to be given to those youngsters in 15 order to then invoke the need for ten samples. I mean, 16 now you've got a research protocol that an IRB needs to 17 look at. So I wouldn't give you the same crisp answer 18 on the ten samples. If they were small samples, if 19 there was a catheter in place so you didn't have to 20 stick them ten times, if there was in a certain 21 situation in a clinical research center or an 22 environment that was comfortable for the kids, I mean, 23 there's a whole host of things. 24 But, generally when you're doing ten samples, 25 you've done it after you gave something to a child in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 123 1 order to invoke the need for serial measures. And, of 2 course, then we would have to look at what are you 3 giving and what is that substance and what does that 4 mean and all those kinds of things. 5 DR. SHAMOO: And there are certain conditions 6 where you would allow such research for healthy 7 children, just the fact that they are siblings of 8 runaways; is that what you are telling me? 9 DR. FLEISCHMAN: There are characteristics of 10 groups of children that warrant IRBs to consider them 11 having a condition that is worthy of examination. 12 Okay. So that's the first hurdle is for the IRB based 13 in an investigator is making a case about why that 14 might be a reasonable thing to do, I don't know the 15 epidemiology of that group of children. But one might 16 -- might -- make the case that the characteristics of 17 that group of children would warrant a research study. 18 Then we would have to get into the specifics of the 19 study, the specifics of the vital importance of what 20 we're going to learn, the specifics of the intervention 21 or the procedure in terms of was it just a little bit 22 more than minimal and then the specifics of the 23 institutional setting and the environment. 24 And after we did all that work, which we 25 should do at our IRB meetings, we would then make a PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 124 1 judgment or we might find that we need to negotiate 2 with that investigator to help that investigator to do 3 a more ethical study. And then we would have to deal 4 with the issues of assent and permission. And assuring 5 that the parents were not feeling coerced because their 6 other child was in an important place getting important 7 therapy and this child, you know, if they didn't get 8 permission might do something for the other child. I 9 mean, we need to deal with each of those issues that 10 you've written eloquently about and you and I agree on. 11 But we would have to do it case-specific. 12 DR. SHAMOO: Well, this is where my answer 13 would be as crisp as your first answer. That kind of 14 research, in my view, should not be allowed because the 15 child is healthy, runaway is not really quote/unquote a 16 disorder, not a condition where there are obligations 17 that we have to use that child for ten blood samples. 18 DR. FLEISCHMAN: Let me just clarify now so 19 we clarify what you're meaning. Runaways might be a 20 condition. Siblings of runaways might not. 21 DR. SHAMOO: That's what I'm saying. 22 DR. FLEISCHMAN: Might not. I don't know the 23 epidemiology. But, I would argue that siblings of 24 diabetics might be a condition. 25 DR. SHAMOO: I agree with you with diabetic. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 125 1 I agree with you obesity. But I'm talking about a 2 social quote/unquote condition which is so broad that 3 you could get any child to qualify for exploitative 4 research. That is my concern. And those, what you 5 have written so far with the definition of condition 6 does not exclude that kind of research. As a matter of 7 fact, if anything, it allows it. 8 DR. FLEISCHMAN: Susan. 9 MS. KORNETSKY: The condition -- I mean, 10 you're looking at the word "condition" but that has to 11 be taken into context within the whole protocol. What 12 is the purpose? I mean, you're making some -- you 13 know, some general-type statements but you can't say 14 yes or no without understanding the protocol, the types 15 of things that -- you know, you would have to explain 16 to an IRB, why runaways? Why not other kids? Why this 17 population? There are so many other questions there 18 that I find it troubling just to make a general 19 statement, you're going to be able to use children. 20 You can't take it out of context. 21 DR. FLEISCHMAN: Okay. We are going to need 22 to move on, so we're going to have Elliot and Felice 23 and then I will turn the chair back to Mary Faith. 24 DR. DORFF: Just a similar comment, namely 25 that I think that if you're talking about runaways, the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 126 1 kinds of research that would be more likely I think 2 would be sociological research of one sort or another. 3 And there the risks would be questions of, you know, 4 privacy and of sharing of information that other people 5 should not have. And there, I think, whoever is 6 supposed to approve this kind of research would have to 7 go into those kinds of risks in terms of that kind of 8 research. 9 DR. FLEISCHMAN: Felice. 10 DR. F. LEVINE: And those are the very kinds 11 of examples that we're seeking to develop for the 12 tables and charts. Your own -- Adil, your own contrast 13 was really not to the -- what we would consider to be 14 the subject of the study, but yours was really to 15 whether it would be appropriate to introduce sibling 16 control groups and obviously that would have to be 17 carefully examined based on the -- what we might now 18 call the relevance standard versus the vital importance 19 standard as to whether studying those siblings -- how 20 we could study them in a way that would be important, 21 noninvasive, of minimal risk and one that would enhance 22 our understanding of that -- 23 DR. SHAMOO: That's a really unfair answer 24 because you just said minimal risk and Elliot's example 25 was also minimal risk. We are talking about greater PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 127 1 than minimal risk. 2 DR. FLEISCHMAN: See, Adil, I think the 3 answer to your concern -- I share some of your concern, 4 perhaps not all of it. I think the answer is in 5 accountability. It's in retrospect of review of the 6 work of local IRBs. I think it's in the whole issue of 7 credentialing and review of IRBs. Because we can do 8 anything, you know, prospectively in telling IRBs how 9 they wished they would behave. But unless we are 10 willing and, you know, OHRP, and the accrediting, not- 11 for-profit agencies are willing to go out and review 12 how it's actually being implemented, we're not going to 13 able to get to the level of assurance that you're 14 raising which I share. 15 You're raising the prospective, if we're more 16 restrictive in the language, then it's less likely IRBs 17 will sin. And I understand that. I do. 18 What I think most of the workgroup in the 19 children's issues are saying, we need to allow certain 20 levels of research in children for the sake of future 21 children. And what we are trying to do is to put 22 fairly good parameters around that and then we've got 23 to go back to those IRBs and be sure they're 24 implementing them in ways that we're proud of. I think 25 that's the difference in the argument from the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 1 28 1 workgroup's perspective and from the perspective that 2 you're arguing. I think we would like to get to the 3 same place. 4 CHAIRPERSON MARSHALL: And as a mechanism of 5 getting to that place, I would like to call on Mark to 6 reiterate his proposal that he made just a moment ago. 7 MR. BARNES: Thank you, Mary Faith. 8 My proposal was, I guess to add two parts, 9 one is that we ask the working group and especially 10 Alan who is the leader of the working group to go back 11 and try to take these -- all the concerns that were 12 expressed and the points of view into account in the 13 next iteration of this draft. That's one request or 14 motion, and the second part of the motion would be that 15 with that understanding that he and the working group 16 will do that, that we approve this interim report and 17 that we ask the working group to continue on the path 18 that it's on. And thank them. 19 And the third part is to thank them. That's 20 right. 21 CHAIRPERSON MARSHALL: All right. Thank you. 22 And so we have a proposal on the table. Just a couple 23 of minutes of discussion and then I'm going to call a 24 vote on this. Bob. Bob and then Abbey. 25 DR. R. LEVINE: Second the motion. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 129 1 CHAIRPERSON MARSHALL: He seconds it. Thank 2 you very much. 3 Abbey. 4 MS. MEYERS: I just want to clarify. This is 5 the beginning of a process. It doesn't address the 6 problem of children who are sick and seriously ill 7 children, and that that is going to happen in the 8 future. That will be added to this; right? 9 CHAIRPERSON MARSHALL: Okay. 10 DR. FLEISCHMAN: Each of our workgroup 11 reports hope to stand on their own. I just want you to 12 understand, we're trying to move this along to OHRP 13 because we think they need to do something. And, you 14 know, we can't produce it much faster, but we would 15 like to. So the next document on prospect of direct 16 benefit will hopefully stand on its own and be moved 17 through this process. So we are not going to hold this 18 waiting for the next piece to be attached is what we're 19 saying. 20 MS. MEYERS: But basically that all children 21 have to be categorized in these two sections that 22 you've written up about minimal risk and small 23 increment. Okay. 24 DR. FLEISCHMAN: We've only spoken to two 25 sections of the regulations and we hope to speak to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 130 1 many of the others that Felice has raised and the 2 remuneration questions, the assent questions, the 3 adolescent consent and assent questions, I mean, we're 4 going to bite them all off, because as the report to 5 Congress said, they need clarification. We are just 6 doing it at a rate as rapidly as we can come to 7 consensus under the present circumstances. 8 CHAIRPERSON MARSHALL: All right. We have a 9 lot of work to do. So brief comment and then feel 10 free, from the floor. Adil. 11 DR. SHAMOO: I need clarification. Because 12 your second point almost is opposite of the first 13 point. First they have to take the concern of this 14 committee and redraft it and bring it back. The second 15 part is really we're blessing the process, not the 16 final draft -- I mean, not the current draft. 17 MR. BARNES: I'm not asking that we bless the 18 current draft. What I'm asking is a motion for the 19 sense of the committee that with the emendations and 20 amendments that we've talked about today, with the 21 suggestions and the directions to Alan and the 22 workgroup that with that included that we bless this as 23 an interim product, but not as a final product and ask 24 the committee -- 25 DR. SHAMOO: Okay. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 131 1 MR. BARNES: -- to continue on their process 2 and thank them for their efforts. 3 DR. SHAMOO: Thanks for the clarification. 4 MR. BARNES: Okay. 5 DR. FLEISCHMAN: Madam Chairperson, can we, 6 within the process of NHRPAC, if we do, do the 7 reiterating, is it possible that we could get an 8 approval prior to the next meetings of NHRPAC through 9 some process other than face-to-face meetings? 10 CHAIRPERSON MARSHALL: Yes. We can do it as 11 we have in other contexts, and that is, send it out 12 electronically and have that sort of discussion. So, 13 yes, we can do that. John. 14 DR. MATHER: John Mather with the VA. I just 15 want to thank you, Alan, and your committee for taking 16 it as far as you have. You may be surprised to know 17 that the VA is involved in 25 of its VA medical centers 18 in childhood research. And I have been amazed at the 19 questions that have come back to us like, well how 20 different is this from adults. And I said, let me 21 remind you as a fully trained pediatric 22 otolaryngologist I was reminded one time children are 23 not little adults. So, you need to, you know, think it 24 through very, very carefully. 25 And I want to support what the motion is that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 132 1 Mark has put on the table. But Madam Chairperson, I 2 think we need to think also about this at sometime or 3 another in a broader context of some -- what Bob Levine 4 was talking about, you know, is more than semantics to 5 take these words and give them meaning. And one of the 6 troublesome parts is, which is the vignette that 7 applies to it, you know, in using these particular 8 words and they're different for adults, they're 9 different for children, they're slightly different for 10 pregnant females, they're slightly different for 11 prisoners, you know, they're slightly different for 12 whether you're talking about clinical trials as opposed 13 to a survey, you know, epidemiological research. 14 So I would commend you the thought at some 15 time or another to spend some time drilling down on 16 what these very words mean for us all. I mean, Bob 17 Levine thought it was very eloquent. You know, the 18 English language is the English language. But some of 19 us come from a different ilk and when you're Scottish 20 it really troubles you. 21 [Laughter.] 22 CHAIRPERSON MARSHALL: Well said, and we do 23 plan to provide those sorts of concrete examples and 24 then ask OHRP to further elucidate and that that should 25 be a continuing process, not something that's a static PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 133 1 event. 2 MS. FISHER: Barbara Lowe Fisher with the 3 National Vaccine Information Center. As a member of 4 the public I'm very concerned that there are strong 5 informed consent protections in these guidelines. 6 Under these guidelines under what circumstances and for 7 what justification, if any, can scientific research be 8 performed on children without the voluntary informed 9 consent of their parents because the research is deemed 10 by the IRB to qualify for an informed consent waiver. 11 DR. FLEISCHMAN: Well, we have not, in thee 12 documents at all addressed the other parts of the 13 regulations that speak to assent, consent, and waiver 14 of consent. It is our hope that we will deal with 15 those as has been importantly addressed in Felice's 16 comments around the adolescents. But our conversations 17 here in these documents do not change or make any 18 recommendations about decreasing the power of the 19 importance of parental permission in anything we've 20 written here. 21 MS. FISHER: But you are going to be 22 addressing that in the future? 23 DR. FLEISCHMAN: We plan to address that in 24 the rubric of assent and permission and the potential 25 questions of when ought the permission of parents be PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 134 1 waived. We will address that. 2 Actually, the working group has addressed 3 that directly vis-a-vis the FDA and the regulations 4 that we are on record as having argued that there are 5 times when parental permission might be waived in 6 specific -- specific situations around adolescents with 7 certain procedural safeguards, so we have already laid 8 out the arguments around that. And we will readdress 9 those questions as we get into asset, consent, and 10 permission. 11 CHAIRPERSON MARSHALL: One last question and 12 then I'm going to call a vote. Thank you. 13 MR. DOYLE: Yes, Bill Doyle from Pittsburgh. 14 I would just like to point out that I've been on the 15 pediatric IRB for about 15 years. It's very 16 specialized. We don't have those pressures, that was 17 brought up here. I have never felt the need to do 18 something. But I do think that we have the right 19 representation. Is there going to be a recommendation 20 that we have some specialty IRBs such as a pediatric 21 IRB, an IRB that deals with some other issue? I think 22 it's very important that a pediatric IRB be constituted 23 at universities that are large enough to constitute 24 them. 25 DR. FLEISCHMAN: Well, I can only say that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 135 1 the workgroup is already on record as arguing that 2 there is a need for pediatric expertise at a meaningful 3 level on every IRB that's going to review research 4 concerning children. We've shared that view that with 5 OHRP and I think in general that is a standard that 6 ought to be fulfilled. We have not gone any further as 7 to specify what that would mean. 8 CHAIRPERSON MARSHALL: So I would like to 9 call the vote then and ask that all of those in favor 10 of the personal that Mark has put on the floor -- I 11 think perhaps say aye would be the best thing to do. 12 All of those in favor? 13 [Chorus of ayes.] 14 CHAIRPERSON MARSHALL: Those opposed? 15 [No response.] 16 CHAIRPERSON MARSHALL: Anyone abstaining? 17 [No response.] 18 CHAIRPERSON MARSHALL: Then the motion 19 carries. Thank you, Mark. 20 And, Alan, I also would like to reiterate the 21 huge debt of gratitude -- the continuing debt of 22 gratitude that we owe you. This is very, very hard 23 work and the working group, your leadership; these are 24 very important conceptual issues. And it's exceedingly 25 hard work. So thank you for the leadership. Thank PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 136 1 those of you who are in the audience who are members of 2 the working group and who are on the committee as well. 3 We will be back to you with words on paper 4 electronically. 5 Kate would like the floor for just a moment. 6 MS. GOTTFRIED: Just with respect to what 7 Alan mentioned regarding waiver, parental permission, 8 and the letter regarding assent. That is on our web 9 site for individuals who are interested in looking at 10 it. The letter that was send to the FDA in response to 11 their proposed adoption of the children's regulations 12 with that particular exception. 13 Also I just want to, on behalf of the 14 committee as well, and the staff, which is myself, 15 yours truly, thank Alan and the entire workgroup for 16 its immense work and all of the -- well, really this 17 was a very laborious process. It is still ongoing. It 18 is incremental and that should be impressed upon 19 everyone here that part of the reason it's a little bit 20 slower than we would anticipate is because we are under 21 resourced. And that is a reality that we are trying to 22 change. But it is a current reality and so we will be 23 biting off these other issues as we can and move 24 forward throughout the year. 25 CHAIRPERSON MARSHALL: And we're sorry that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 137 1 Dr. Koski was not here for this part of the discussion, 2 but we will certainly reiterate it later. Yes. 3 So I would like to move, we as a committee, 4 at our last meeting voted to weigh in on the HIPAA 5 regulations as they pertain to human subjects research 6 and we have been busy. I would like to call on Mark 7 Barnes to update the committee on what we have done and 8 sort of continue our discussion about that. 9 Mark, thank you. 10 MR. BARNES: Mary Faith, could I say one 11 thing just about the children's workgroup? 12 Alan, I would think that you and the 13 workgroup, given that you're doing so much work and 14 that you're actually in a systematic way going through 15 all of these different research issues and Common Rule 16 issues regarding pediatrics, I would encourage you guys 17 really to think about an article at the end of this 18 that really outlines, you know, that sets forth in a 19 very coherent way all of the work that you've done, 20 because I think that would be of enormous use to 21 everyone, not just as a report from the committee that 22 actually has an article. 23 [Laughter.] 24 CHAIRPERSON MARSHALL: And we know who is 25 good at putting words on paper on this group. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 138 1 MR. BARNES: Right. Okay. Thank you, Mary 2 Faith. 3 We have had sort of a rolling discussion over 4 the past, I guess, maybe four or five months about the 5 issue of the privacy regulations under the Health 6 Insurance Portability and Accountability Act and the 7 potential impact of those regulations which will go 8 into effect in April of 2003 is the enforcement or 9 compliance date on the conduct of human subjects 10 research. We talked about it. We had a presentation, 11 I guess, about four or five months ago from Julie 12 Kaneshiro [ph] who was -- who I think is here today -- 13 Julie, are you here? 14 CHAIRPERSON MARSHALL: Julie. 15 MR. BARNES: There she is. 16 Julie had been gracious enough to give us a 17 presentation and Julie had been working inside HHS on 18 the inner working group that was looking at the HIPAA 19 privacy regulations and the potential amendments to the 20 privacy regulations. And then we had a letter that we 21 had floated in advance of what was actually an official 22 publication on March 27th of this year of what's called 23 the "Notice of Proposed Rule Making" or an NPRM, 24 whereby HHS working, Julie and the others working 25 within HHS had determined that a series of amendments PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 139 1 ought to be made to the privacy regulations for a 2 number of purposes and therefore they proposed in the 3 Federal Register with a 30-day comment period that has 4 just closed on April 26th, a series of amendments to 5 the privacy regulations that would accomplish a number 6 of things. 7 These are only proposals and there was the 8 comment period and then probably we won't see a final 9 kind of publication of these regulations until 10 sometime, I would say, in my estimation, although, 11 Julie, please, if you have other information then we 12 would love to hear it, I would be looking forward at 13 the earliest in the late summer and probably sometime 14 in the fall of this year. But that's my outside extra 15 HHS perspective on it. 16 Before I go ahead, Julie, do you want to make 17 any comments about sort of the process or where it 18 stands or how many comments were received or any kind 19 light that you could shed on the process of the 20 publication of the NPRM? 21 CHAIRPERSON MARSHALL: And we're putting you 22 on the spot, Julie, but could you do it at the 23 microphone? 24 MR. BARNES: And if you don't want to, you 25 don't have to. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 140 1 [Laughter.] 2 CHAIRPERSON MARSHALL: We would never coerce 3 anyone. 4 MS. KANESHIRO: I'll give you my verbal 5 informed consent. 6 We did complete the public comment process, 7 as you mentioned, on Friday the 26th. And I'm really 8 not certain how many comments we received. We were 9 expecting in the order of, you know, several tens of 10 thousands -- or, sorry, tens of thousands of comments, 11 but I really don't know the final count. I imagine 12 we're still going through them. 13 We do expect, as Mark mentioned, to publish 14 final rule in response to those public comments 15 probably towards the end of the summer, but it really 16 is difficult to say at this point given we haven't seen 17 the substance of what those comments are and the amount 18 of policy thinking that we'll have to be doing over the 19 coming months. 20 But I thank you for your comments on the 21 rule. 22 MR. BARNES: Oh, thank you, Julie. And 23 people should know that Julie actually -- we're lucky 24 at OHRP and NHRPAC that Julie has now moved over to our 25 staff at OHRP and NHRPAC. So I know that Greg is glad PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 141 1 to have her on board. 2 So what occurred is that we were in the 3 process of actually trying to comment on the problems 4 we saw with the HIPAA regulations and then in the 5 middle of our process of commenting the NPRM came out 6 which actually answered some, but not all of the 7 concerns that we had expressed in our original draft 8 letter. And, therefore, Mary Faith had asked me to 9 redraft the letter that had already been approved by 10 this committee trying to take into account the fact 11 that some, but not all of our concerns had been 12 answered by the NPRM. 13 I should point out also that in the NPRM 14 probably about a third or maybe even 40 percent of the 15 NPRM actually was devoted to issues of human subjects 16 research and the impact of HIPAA on human subjects 17 research which I think is good. It shows that HHS is 18 listening and it also shows that the national research 19 community was speaking up about the issues and the 20 problems. And I would like to think that we had some 21 impact on the process of the formulation of the 22 proposal. 23 We therefore did send a letter which I think 24 it's fair to say was completely consistent in tone, and 25 in substance with the letter that had been approved PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 142 1 before that had been worked on, circulated throughout 2 the committee, worked on by a subcommittee which 3 consisted of Adil, Sandy, myself, and Bob Rich. And 4 was there anybody else on that little subcommittee? 5 Was Judy on -- Judy, were you on -- no, okay. So if I 6 missed anybody, I'm sorry. 7 And we had worked on it to try to hammer out 8 a kind of consensus document. The difficulty frankly 9 in hammering out a consensus document among this 10 committee is that there were people on the committee 11 who took radically different views of the world of 12 HIPAA as it applies to human subjects research. There 13 were some on the committee who took the position that 14 in fact human subjects research because it is regulated 15 by the Common Rule and the Common Rule requires 16 consideration by the IRB of privacy and confidentiality 17 information that therefore HIPAA should not actually 18 apply to human subjects research. 19 There were others who thought that the 20 standards that HIPAA applied were not strict enough in 21 protecting research subjects. And so what we tried to 22 end up with here, and I think what we did end up with 23 was a document that recognizes that the likelihood is 24 that HIPAA will apply to human subjects research and 25 therefore how can we make it workable for researchers, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 143 1 but still protective for research subjects? And that's 2 what I think this document tries to set forth. 3 Let me just make a few comments about the 4 content of the document briefly. Just to take you 5 through the points in the document and I'll try to be 6 quite brief about this. 7 One is that there is a lingering concern 8 about the ability, or the way in which HIPAA privacy 9 rules would allow or not allow institutions to compile 10 patient data and also data connected to patient tissues 11 or patient specimens which are not collected for the 12 purpose for a particular research project but rather as 13 a database that could later be mined for particular 14 research projects. And the way that I think the better 15 reading of the HIPAA privacy regulations as they stand 16 now, and including the way that the NPRM looks, it's 17 not exactly to me clear as an attorney who does advise 18 IRBs and research institutions that in fact that this 19 kind of pre-research use of data would actually be 20 allowed. 21 And so one of the things that we specified is 22 that there should be a process for approving by which a 23 privacy board or somebody or some entity could actually 24 look at these issues and approve the compilation -- the 25 pre-research compilation of data. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 144 1 The second issue was the problem of the 2 potential that a subject, once they -- if they 3 experience that they -- if they enrolled in a trial 4 with full informed consent and experience an adverse 5 event, they may decide, in fact many do decide and for 6 understandable reasons, to in fact pull back and not 7 continue in the study because they had experienced an 8 adverse event. 9 The difficulty is that under HIPAA when they 10 revoke their consent to participate in the study, they 11 also could revoke their authorization under HIPAA to 12 allow the researcher and the research team, and the 13 sponsor to continue to use the data even about their 14 adverse event. 15 If that occurred and there were a revocation 16 not only of consent for the research, but also 17 revocation of the data -- of the authorization to use 18 the data, then the actual experience itself of the 19 adverse event which could be extremely beneficial for 20 medical science and for people with that condition that 21 would be basically off limits for the use -- continued 22 use by the research team which we thought was really 23 not appropriate. And therefore we recommended that 24 there be actually a process by which the continued use 25 of data might be in those situations, could be reviewed PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 145 1 by the privacy board or the IRB and could be approved 2 in that sense. 3 And, in fact, I understand, in fact, directly 4 from some HHS staffers that that was -- that this was 5 in fact -- it has been of great receptivity on the part 6 of HHS to this particular recommendation of NHRPAC. 7 The third issue was the duration of the HIPAA 8 authorization and that is that under HIPAA an 9 authorization that would be signed by the research 10 subject would have to have a termination event. And 11 the difficulty with a termination event in the context 12 of human subjects research is that research data often 13 has to be used -- often there's a need for researchers, 14 sponsors, and the FDA to use the research data long 15 after the actual research has ended and the apparently 16 final publication of data had been accomplished. And 17 so HHS and the NPRM had tried to get around this by 18 saying, well, you can simply put in the authorization 19 form the idea that the authorization would end at the 20 termination of the research. 21 But what we pointed out in our letter is that 22 that really is not good enough and we made an alternate 23 formulation suggestion to HHS in terms of a defining 24 event as being the termination of the research project 25 or the extinguishing of the need to review, analyze and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 146 1 consider the data generated by a research project, 2 whichever is later, as being an appropriate termination 3 event. 4 The fourth point is that we actually praise 5 HHS for eliminating the distinction in the NPRM between 6 the category of research not involving treatment and 7 research involving treatment which in many ways greatly 8 complicated the final regulation that was issued at the 9 end of the year 2000. 10 The fifth point which had a lot of hot 11 discussion among the committee was a somewhat obscure 12 but a very important point which is that under the 13 strict reading of the HIPAA regulations one's treating 14 physician actually could not talk to a patient about 15 the possibility of the patient enrolling in a clinical 16 trial because that very conversation would be a use or 17 disclosure of data which would not be allowed under the 18 terms of the patient's consent to the HIPAA practices. 19 The reason for that is that research is not treatment, 20 it's not payment, and it's not health care operations 21 which are the only things, the only purposes for which 22 health care providers could actually use and disclose 23 data. 24 It also means that the health care provider 25 could not discuss with colleagues who have clinical PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 147 1 trials the eligibility of that particular person's or 2 physician's patient for trial even if the patient 3 wanted to enroll in trial. And what that would 4 necessitate therefore would be that before a physician 5 could actually talk to another clinicians about a 6 patients eligibility they would have to go back to the 7 patient in each and every circumstance and get a new 8 signed authorization from the patient allowing the next 9 discussion to occur, which clearly would clog the mills 10 of patient enrollment into clinical trials. And these 11 are clinical trials that patients in many cases want to 12 get into. They're trials of people who are really 13 quite eager to enroll in oncology studies or AIDS HIV 14 studies or other studies. 15 Therefore, we recommend actually two 16 different possibilities. One is that these, the 17 treating clinicians be allowed under regulations to 18 communicate with other physicians or other researchers 19 who are conducting clinical trials with two conditions. 20 One is that the information discussed between the 21 treating physician and the clinical investigator would 22 be the minimum necessary to try to investigate the 23 patient's eligibility for a trial without -- and 24 hopefully therefore and without revealing the name, 25 because one can't imagine that the name would actually PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 148 1 be necessary to have the eligibility discussion. And 2 the second would be the stipulation that the clinical 3 investigator to whom the information would be disclosed 4 would himself or herself be bound by HIPAA privacy 5 obligations as part of a covered entity. So they would 6 not be able therefore to redisclose the information 7 without specific authorization from the patient or 8 subject. 9 That was one suggestion we made. 10 The other suggestion that we made would be 11 actually to have a process that would be sanctioned by 12 -- would be allowed by the final HIPAA regulations so 13 that a patient and a physician could have a discussion 14 up front about whether the clinician -- about whether 15 the patient wants the clinician to have those 16 eligibility discussions and the patient would be able 17 to execute a kind of blanket authorization for that 18 process of discussion so they would not have to come in 19 the office each time and sign a new authorization. But 20 in order to have such a blanket authorization it would 21 require actually a change in the HIPAA regulations. 22 The sixth point is that we endorsed and 23 thanked HHS for reducing the waiver criteria for the 24 waiver of the HIPAA authorization. They reduced it in 25 the NPRM from eight criteria to three criteria. The PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 149 1 three criteria being minimal risk and the actual -- the 2 impracticability of gaining an authorization from 3 patients or subjects. We said that that was actually a 4 very welcome development because it greatly simplifies 5 -- it's a more accurate way of looking at the issues, 6 we thought and it certainly simplifies the lives of 7 those who have to apply these criteria on either an IRB 8 or a privacy board. 9 And finally we asked HHS to look at the very 10 rigorous standards for deidentification of data. There 11 was a part of HIPAA which says that if 18 different 12 data categories are shed out of clinical data, then the 13 deidentified information can be used and disclosed 14 freely for research purposes or for any purpose 15 actually, even for marketing purposes. And there has 16 been a lot of consternation among the research 17 community because the datasets, the 18 datasets are 18 actually so extensive, meaning that in some cases the 19 data that would be left would not actually be usable 20 for some research studies. 21 So we, although not making some very specific 22 suggestions, we know that many, many entities and 23 people have made suggestions for which of the 18 24 categories they would allow to be left in the data and 25 it could still be regarded as deidentified. We PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 150 1 certainly say that it ought to be what ought to be 2 looked at least is the issue of zip code and address as 3 being important for epidemiologic and public health 4 studies, particularly in regard to environmental 5 exposures and development, for example, of cancer among 6 certain populations geographically defined. And that 7 basically is our letter which was delivered on April 8 24th to HHS. 9 CHAIRPERSON MARSHALL: Fait accompli. Abbey, 10 I'm just going to allow a couple of minutes because 11 we're over time and it's lunchtime. 12 MS. MEYERS: Well, I just want to put it on 13 the record officially that I abstained from signing on 14 to this letter. I think there is nothing in my memory 15 that has made the patient community more angry than the 16 fact that HHS has taken away the confidentiality thing 17 by requiring -- taking away the requirement that 18 patients consent -- give their written consent up front 19 and it has infuriated a lot of patient community. 20 There is a sentence in here that says, "The 21 individual members of NHRPAC have come to understand 22 and appreciate in a direct, first-hand way some of the 23 problems associated with the implementation of the 24 HIPAA rules in the context of research involving human 25 subjects." PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 151 1 And I have to say that I think there's only 2 two of us on this panel who are consumers and we're not 3 in the business of research. That the people I hear 4 from are the women who had a baby out of wedlock at the 5 age of 15 and gave it up for adoption and don't want 6 their husband and children to find out. Or the 7 politicians who have a serious mental illness diagnoses 8 and know that they'll never win an election and want to 9 keep it secret. And the pilots, and the teachers of 10 children, and they're the ones who are saying, how 11 could this have happened. So that's why I could not 12 sign on to this. 13 I think that the patient community is so 14 furious that they've taken away the requirement for our 15 written permission that this information will be able 16 to get out to anybody who wants to have access to our 17 records. I think it's a terrible thing and I think 18 that if the HHS is smart, they will understand how 19 angry people have gotten over this. Because it has 20 been so many years that we've been fighting for medical 21 privacy and they've taken it away just by simply 22 issuing a Federal Register notice. 23 [Applause.] 24 MS. MEYERS: Thank you. 25 CHAIRPERSON MARSHALL: Thank you, Abbey. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 152 1 Alan, did you -- 2 DR. FLEISCHMAN: I think I'm going to have to 3 rise to comment on that which I wasn't planning on 4 doing. But I just don't read these complex regulations 5 with that same concern. I think the intention was well 6 served to protect privacy. It still can protect 7 privacy and still allow important work to continue. 8 But the reason I raised my hand is to comment 9 that we owe an incredible debt of gratitude to Mark. 10 If NHRPAC, in my opinion, thinks the children's 11 workgroup did hard work, not even a log difference. 12 Since there are only eight people in the United States 13 who truly understand the HIPAA regulations -- 14 [Laughter.] 15 DR. FLEISCHMAN: -- and we're lucky enough to 16 have one of them over there and another one of them 17 OHRP now, I really think we are in Mark's debt and the 18 United States is in his debt for having really 19 carefully thoughtfully crafted some comments that I 20 think are incredibly helpful. 21 CHAIRPERSON MARSHALL: Yes. Just so. We 22 should have applause. I will second that motion as 23 well. 24 [Applause.] 25 CHAIRPERSON MARSHALL: The folks who are at PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 153 1 the podium and then we will break for lunch. 2 MS. KANE: I'm a private citizen who did read 3 the 1,500 page medical privacy regulations and I have 4 to say I'm also an attorney, but I don't do this as my 5 practice. I'm just doing this because I'm a concerned 6 private citizen. And I have to tell you, I do not know 7 how -- 8 CHAIRPERSON MARSHALL: Could you tell us who 9 you are? I'm sorry. 10 MS. KANE: My name is Robin Kane. 11 CHAIRPERSON MARSHALL: Thank you. 12 MS. KANE: I don't understand how we can have 13 a medical privacy regulation in which we remove the 14 written patient consent forms. To me that is just 15 mutually exclusive. 16 And what has happened here in the recent 17 proposed changes by the federal government is that 18 they're taking away the very mild consent provision 19 that the Clinton administration had put in and there 20 will be an ability for patients to go to doctors now 21 and for purposes of health care treatment, payment, and 22 what's called health care operations, you will no 23 longer be provided with the written consent form that 24 you sign before your medical records are released. 25 Instead, you will be given an authorization, basically PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 154 1 notice, of who the doctors are going to share your 2 information with. That puts the federal government and 3 doctors and others in the driver's seat, not the 4 patient, who goes to the doctor and tells such personal 5 information to be healed, not to be revealed. And it's 6 a limited use, basically. You go to your doctor so 7 that he can heal you. 8 But what's happening now is we're removing 9 the patient consent forms and instead the federal 10 government through its Office for Civil Rights can go 11 to any doctor's office or hospital without prior notice 12 or a subpoena, or the patient's consent, or the 13 doctor's consent, and go in and track those medical 14 records, get access to the medical records. We also 15 have health researchers, law enforcement, public health 16 officials, countless others getting access to this 17 information again without the patient's consent. So 18 what we've done is substituted regulatory permission 19 rather than patient permission. 20 So I'm here to make, you know, I basically 21 stand here for the thousands of people that did send 22 comments to the federal government and say, "what about 23 the little man?" It seems that the health care 24 industry has prevailed here. Perhaps through, you 25 know, campaign contributions or perhaps through other PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 155 1 means and reasons, I cannot say. But I think that the 2 patient's rights should be considered first and 3 foremost. 4 Thank you. 5 CHAIRPERSON MARSHALL: Thank you very much. 6 I appreciate that. You know, my area of 7 research in the past has been perinatal substance abuse 8 and I have serious concerns about privacy or lack 9 thereof and the impact that it can have on people's 10 lives. 11 John. 12 DR. MATHER: John Mather with the VA. Mark, 13 I do think this is a contribution and a positive 14 contribution to the getting issues on the deck. And I 15 think further than that, along with all the other 16 contributions we made somewhere it will filter out. 17 For the health care system that's at VA, of course, 18 it's not just where research goes on in one facility, 19 it's what that permission might mean for rippling 20 across to other facilities. 21 And more especially, the only area I think 22 it's weak is in part three where it's alluded to, but 23 the issue of repositories and depositories of data. 24 And what is the necessity for protecting those 25 particular sets of data. I mean, we talked literally PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 156 1 about biological specimens and such repositories or 2 depositories. But when you talk about data and it's 3 sort of kept on line, and so on, you hint at it in part 4 three, but you don't come right out and deal with that, 5 I think, as an issue. Really for us in the VA, that's 6 a very significant issue because you can imagine data 7 being dumped into depositories with all kinds of 8 identifiers on it. And if it's not clearly identified, 9 then probably somebody needs to give a second consent 10 to that data being used. Then what is that 11 depository/repository of data? 12 You get to it a little bit, but I think, 13 Madam Chairperson, it's something, not just in respect 14 to data and HIPAA, but also biological specimens, this 15 issue is, who owns that when the experiment is over and 16 terminated and done. It sits there somewhere. Is it 17 automatically to be destroyed? Or if it is valuable in 18 the public interest, not just the public data set, but 19 in the public interest, what is it that it means for 20 those individuals who have been enrolled as human 21 subjects in that part -- need to be reapproached again 22 or maybe approached up front. We're going to put that 23 is into a repository/depository. I think there's only 24 one weakness in your letter in that regard. 25 CHAIRPERSON MARSHALL: Thank you. I think PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 157 1 Mark probably would like to respond to that. 2 MR. BARNES: Yes, I take your point. I think 3 that one of the issues -- when HIPAA -- when you try to 4 understand how HIPAA applies to human subjects 5 research, it turns out that really it casts into doubt 6 or raises questions about the ways in which we are 7 conducting human subjects research and about data 8 practices, you know, in general. And one of the issues 9 that is touched on in here, but is not fully outlined 10 or discussed is this issue of whether there ought to be 11 IRB approval for the pre-research compilations of data 12 and whether there ought to be actual informed consent 13 for a person to have their tissue or their information 14 put into a kind of pre-research data platform or tissue 15 bank platform. 16 The practices -- you know, my impression, and 17 I actually talk about this in an article I published 18 about a week in BNA which is about the effect of the 19 NPRM on human subjects research and I treat this issue 20 more fully there. I didn't feel like I had latitude to 21 treat it here because we really didn't have a -- we had 22 not discussed it among the committee. But one of the 23 things I say in my article and I do believe is that I 24 think that people really, IRBs and institutions really 25 do need to clean up their act in regard to how and why PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 158 1 they're conducting these pre-research compilations of 2 data. And there needs to be, really, I think some kind 3 of national policy about it or some kind of guidance 4 from OHRP. Particularly because IRBs are splitting all 5 over the place and in many cases they are simply 6 following widely varying state law, state law 7 requirements, and all of which really doesn't add up, I 8 think, for adequate, you know, understanding or 9 oversight as to what these databases are being used 10 for. 11 So I agree with you. 12 CHAIRPERSON MARSHALL: Thank you, Mark. So 13 brief, please. 14 MS. BLEVINS: I read the rule as well, and I 15 think it's important to recognize that if you are here 16 to protect humans, you are not fulfilling your mission. 17 And I say that in that having read every single word 18 of the proposed rule and then the final rule, and then 19 also the proposed revisions, every one in here, if any 20 of you have a secret, if any of you have ever consented 21 to anything in your past, if any of you have ever been 22 to marital counseling, psychological counseling, had an 23 STD, anything, that information will be available to 24 others. 25 The consent that you gave in your past is PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 159 1 being eliminated. And I really want to encourage you, 2 I'm here to support you and to tell you that I support 3 research in humans and if you force people to hand over 4 data without their consent they will do one thing, they 5 will lie and all research in this country will be based 6 on a database of lies and that will be very, very 7 unfortunate for the research community. Thank you. 8 CHAIRPERSON MARSHALL: Thank you. And I'd 9 like to observe that if we -- I think we will have some 10 extra time between 3:00 and 3:30 this afternoon and 11 that if we want to resume this discussion that we can 12 revisit there. Because I want people to feel as though 13 there is ample time to discuss something that there is 14 serious concern over. 15 So, thank you very much. 16 Sure, Mark. Mark can have the final word 17 before I have the final word. 18 MR. BARNES: One thing I want to point out. 19 I mean, I understand this issue of written consent or 20 not written consent which actually went back and forth. 21 The Clinton administration first proposed no written 22 consent and then in the final rule they came out with 23 written consent, and then the Bush administration has 24 proposed pulling back on it. I understand that that's 25 a great subject of controversy, but I should point out PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 160 1 that what we're saying and what we put in this letter 2 is really true regardless of whether there is written 3 -- the requirement of written consent or not the 4 requirement of written consent at the first entry of 5 the patient into the health care system. Because what 6 we're talking about applies to all the regulatory 7 regime and rules that would survive. 8 So I'm not -- I mean I have my personal 9 feelings about written consent or not written consent. 10 But I do want to point out that we are not -- we don't 11 treat that issue per se in here. And, in fact, what we 12 try to do here is we do try to preserve patient choice 13 while also allowing human subjects research to proceed. 14 CHAIRPERSON MARSHALL: Thank you very much, 15 Mark. We can't thank you enough for your hard work. 16 I also want to thank you for observing that 17 the government has determined that research is not 18 treatment and those of you in the room who work at the 19 NIH, perhaps you could convey that notion back to them. 20 I've always been opposed to their use of treatment 21 rather than intervention or something like that in 22 their informed consent documents. 23 We have had an interesting morning. We are 24 going to have, I think, an interesting afternoon. I 25 want to pick up a few key words from our conversation PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 161 1 this morning that as a group, and I'm being inclusive 2 of everyone in the room here, a group of delusional 3 policy wonks who have zany, but specific, conversations 4 about nothing that we will resume that activity at -- 5 [Laughter.] 6 CHAIRPERSON MARSHALL: -- and of vital 7 interest, we will resume that activity at 1:00 in this 8 room. 9 Thank you all very much. 10 Kate needs to speak to committee membership. 11 MS. GOTTFRIED: I need Judy Siegel, Abbey, 12 Susan, Bob Levine, and Elliot. 13 [Whereupon at 12:17 p.m., the meeting was 14 recessed to reconvene this same day at 1:00 p.m.] 15 PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 162 1 A F T E R N O O N S E S S I O N 2 [Time noted: 1:15 p.m.] 3 CHAIRPERSON MARSHALL: We are going to 4 reconvene in about two minutes. Thanks for your 5 patience. 6 Well, I hope you all managed to wolf some 7 nourishment down in the short time that we've had. 8 Thank you for being back. Those of you who are back on 9 time. 10 We are going to begin. It should be an 11 interesting afternoon. I had the opportunity in the 12 interim between our last meeting and this meeting to 13 attend a meeting in New York that was organized by the 14 Mount Sinai Center for Children's Health and the 15 Environment and was co-sponsored by the New York 16 Academy of Medicine. And I thought the theme of the 17 meeting which has to do with policy approaches to 18 pesticide testing in humans was something that might 19 interest the committee and talked to Kate about it. It 20 certainly does involve health policy in research with 21 humans and I thought that you should know about it and 22 that we should have a conversation about it. So we 23 have invited a number of folks to present to you this 24 afternoon on this issue. 25 We are going to begin with William Jordan who PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 163 1 is Senior Policy Advisor, Office of Pesticide Programs 2 at the Environment Protection Agency. And we welcome 3 you to the table and look forward to a fruitful 4 afternoon. Thank you so much for being here. 5 MR. JORDAN: Thank you, Dr. Marshall. I 6 really appreciate the opportunity to be here with you 7 today and to provide a little bit of background on what 8 is a very controversial and complex issue. I assume 9 that you figured out from the agenda that I'm a lawyer, 10 I'm not a scientist, I'm not an ethicist, I've been 11 working in the pesticide program for about 25 years. 12 So I know a lot about pesticide regulation and my hope 13 is to provide from that information some background 14 that will help you understand the issues that are going 15 to be debated ably by the members of the panel that 16 will follow my remarks. 17 I have only been working on this issue for 18 the last couple of months. So I don't think I'm 19 qualified at this point to talk about the merits of the 20 testing, but I do know and do understand the context 21 within which we are tackling the questions, and so 22 that's what I want to try to provide for you this 23 afternoon. 24 First thing to make clear is that EPA is 25 committed to protection of human subjects. We have PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 164 1 adopted the Common Rule as have other federal agencies. 2 We have a record in that regard that we're very proud 3 of. And we take very seriously the issues that have 4 been grappled with over the years and reflected in the 5 Common Rule. 6 We are also committed to using the best 7 possible science in making our regulatory decisions. 8 We don't see the issues of using good science and 9 protection of human subjects as being in any way in 10 conflict. We think, in fact, the best science is the 11 kind of studies that involve rigorous, careful 12 protection of human subjects. 13 Today's focus is on pesticides. But just a 14 footnote to point out. There is a policy that EPA has 15 announced recently that we will not be looking at 16 certain kinds of human studies and that is the focus of 17 a good deal of the controversy. It is not limited to 18 pesticides. It is a policy that involves all of the 19 EPA's work in regulatory matters. But since the topic 20 for today is pesticides that's where I want to start. 21 Most of you have, I'm sure, the same kind of 22 image that I did when I first started working in 23 pesticides and that is pesticides are the things that 24 farmers use. They're the insecticides, the weed 25 killers that are sprayed on the fields, amber waves of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 165 1 grain, and tomatoes and so forth. And that is, in 2 fact, a large part of the universe of pesticides, but 3 it is by no means the only type of product that is 4 included in this category. And I hope that when you 5 think about this subject and ask questions and sort of 6 ponder where to go that you'll remember that there are 7 lots of other kinds of products. 8 Well, of course, there's the things that we 9 use to kill the cockroaches around the house. There 10 are products that are used to kill the weeds along the 11 highways and there are a very large number of 12 fungicides that are used to keep the cooling towers 13 that are working with air conditioning in nuclear power 14 plants and industrial operations free of slime in the 15 pipes. There are fungicides for killing mold and 16 mildew in paint products. 17 We have a whole range of public health 18 products that we regulate, disinfectants and sanitizer 19 products that are designed to control mosquitos that 20 spread west nile virus, for example. Products used in 21 swimming pools to kill the germs or hot tubs to kill 22 the microbes that might be disease carrying agents. 23 Rodenicides and on and on. 24 So the universe of pesticides is actually a 25 very large variety of products. And it's also PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 166 1 important to bear in mind that the types of chemicals 2 that can serve as pesticides or materials, I should 3 say, are also pretty widely varied as well. There are 4 microbes that can serve as pesticides. 5 There are, of course, conventional chemicals, 6 some of those conventional chemicals can be used for 7 industrial purposes as well, and, in fact, some of the 8 chemical substances have both pesticidal use and 9 pharmaceutical use. Lindane and malathion are two 10 relatively familiar pesticides that also are used in 11 human drugs. 12 We regulate this universe of pesticides under 13 two different laws, one of which you may already be 14 well familiar with, the Food, Drug and Cosmetic Act. 15 The other has one of those peculiar Washington 16 acronyms, it's called the Federal Insecticide, 17 Fungicide and Rodenticide Act and that's abbreviated 18 FIFRA. 19 I digress here, but it seems appropriate for 20 a human subjects discussion. My favorite mistake in 21 transcripts was when I read through the transcript and 22 somehow that came out as Federal Insecticide, 23 Fungicide, and Genocide Act. 24 [Laughter.] 25 CHAIRPERSON MARSHALL: I was wondering PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 167 1 whether you included husbands under that category. 2 [Laughter.] 3 PARTICIPANT: You will get yours. 4 CHAIRPERSON MARSHALL: I've already gotten 5 mine, this is merely self defense. 6 MR. JORDAN: Both laws are based on a 7 premarket approval system. That is to say, before 8 anybody may sell a pesticide product in the United 9 States, they have to come to EPA and get a 10 registration, a license, for the specific product, for 11 the specific way it's going to be used, and that we 12 issue under FIFRA. 13 The other law, the Food, Drug and Cosmetic 14 Act is directed at pesticides residues in food. And 15 under that law we set what are called "tolerances" or 16 "maximum levels" that are allowed for a pesticide in 17 food. And if there is no tolerance then the food is 18 considere adulterated. So in both cases a company that 19 wants to sell a product or somebody who wants to use a 20 product needs to come to EPA and get an approval from 21 EPA before they may do so. 22 And our approvals are based on a very 23 comprehensive set of information. Next to 24 pharmaceuticals or perhaps maybe even equal with that 25 category of products, pesticides are studied more PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 168 1 extensively or as extensively as any chemical substance 2 that you can think of. We have somewhere in the 3 neighborhood of 25 different animal toxicity studies 4 that we routinely require for a food use pesticide. 5 That's just to evaluate the potential effects of 6 mammalian systems and then we also have an abundance of 7 information about exposure, about effects on wild life, 8 water systems and so forth. 9 The laws that we regulate under have 10 different statutory standards. And I want to take a 11 moment or two to talk about the standards. The Food, 12 Drug and Cosmetic Act is a standard that you may have 13 heard about in other contexts because the same thing is 14 used for food additives. It's a reasonable certainty 15 of no harm. 16 In other words, EPA needs to be confident 17 from the information that we have that the presence of 18 pesticide residues in food, together with other 19 exposures to the general population will not cause harm 20 and we have to have a reasonable level of certainty 21 about that conclusion before we may establish a 22 tolerance. 23 The decision under FIFRA is a little 24 different. It is -- the statutory phrase is 25 unreasonable, adverse effects. We may not approve a PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 169 1 pesticide unless we are convinced that it will not 2 cause unreasonable adverse effects. 3 The law goes on to define unreasonable 4 adverse effects as involving a balancing of risks and 5 benefits. And I think that reflects the congressional 6 judgments or certainly the legislative history makes 7 this point that pesticides products are used because 8 they have benefits, because people want to get rid of 9 the insects, or the weeds, or the mold or mildew and 10 yet at the same time these substances because of their 11 biological activity are also likely to have some risks 12 as well. And we need to understand the risks and make 13 sure that those risks are outweighed by the potential 14 benefits that society gets. 15 Since there are different standards, there's 16 a need to coordinate the two laws together. And 17 basically the way that we do that is that we make 18 certain that any residues in food will not have any 19 harm, potential harm to the society and then other 20 kinds of questions, perhaps wildlife effects, we may 21 look at risk benefit balancing kinds of issues. 22 As I suggest in my remarks, our concerns are 23 not limited just to human health, but include also 24 effects on wildlife, ecological systems, we focus on a 25 wide range even in the human health arena, a wide range PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 170 1 of exposed groups from people who eat food or drink 2 water, to people who handle, mix, load, and apply the 3 pesticides, people who are bystanders who might be near 4 or re-enter a site that has been treated with a 5 pesticide. We are concerned about a wide range of 6 effects. Not only effects that would result from 7 single exposure, but also what consequences might 8 result from a lifetime of exposure either in the 9 workplace or as a result of residues and food. 10 And, it's also fair to point out that our 11 issues also include the efficacy of public health 12 pesticides. If you go to a hospital you want to know 13 that the disinfectants that have been used on the 14 medical instruments actually work. It would be 15 disastrous if they don't. And, in fact, we found some 16 situation where people have proposed to us products 17 that were far less efficacious than they should have 18 been. 19 So that's the backdrop, that's the regulatory 20 system, if you will, for the pesticide program. And I 21 want to talk now about how human studies fits into 22 that. As I said at the beginning, we require a very 23 extensive database on chemicals before we are in a 24 position to make a decision on them. We require 20 25 different toxicity studies for evaluating mammalian PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 171 1 effects, another 60 one-to-one 80 different studies to 2 evaluate other types of ecological system, residue 3 levels in food, physical and chemical hazards among 4 others. 5 Generally speaking EPA does not require -- we 6 certainly do not encourage studies that involve 7 intentional dosing of human subjects. We have received 8 data from time-to-time over the years on a wide variety 9 of studies that have involved human subjects and I want 10 to just give you a feel for the variety of products. 11 This is roughly in the order in which we get them. 12 The most that we get are generally on 13 exposure. Passive dosimetry or biomonitoring studies. 14 We get a fair number of studies on efficacy of insect 15 repellents and stuff that you spray to keep mosquitos 16 off of you, we get occasional studies on skin 17 irritation and skin sensitization, or photo 18 sensitization. This is typically for the products that 19 are applied or intended to be applied directly to 20 humans such as insect repellents. We get a number of 21 studies on the efficacy of personal protective 22 equipment, gloves, aprons, masks, that sort of thing, 23 to see how successful they are in reducing potential 24 exposure. 25 We do occasionally, although far less often, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 172 1 get pharmacokinetic studies, and then occasionally we 2 get human toxicity studies; studies where human 3 subjects have been dosed intentionally in a laboratory 4 setting to evaluate what level will elicit some sort of 5 adverse toxic response. 6 We get epidemiological studies, and then we 7 have follow-up on incident reports. 8 As I said, with the exception of the exposure 9 in efficacy studies, and things related to protective 10 equipment, most of these are not required. And so it 11 is relatively rare that we will get these other 12 studies. 13 Human studies represent altogether less than 14 1 percent of the studies submitted a year. And the 15 subunit of that group that involved intentional dosing 16 to establish toxicity is less than half a percent most 17 of the time. 18 The Common Rule applies to any studies that 19 EPA sponsors or conducts. But in addition to that, 20 studies that are conducted by third parties say, 21 companies that are trying to obtain an approval for 22 pesticide registration are also subject to a provision 23 in FIFRA that requires -- that makes it unlawful for 24 any person to use a pesticide in a test with human 25 subjects unless the participants are, first, fully PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 173 1 informed; and, secondly, voluntarily consent to 2 participate in the study. 3 In the past we have used this authority to 4 take enforcement action where we have discovered 5 violations of this particular provision. 6 So, against that backdrop, why the 7 controversy? 8 In July 1998, the environmental working group 9 issued a report which appears in the binder that you 10 all have called the "English Patients" -- that was a 11 popular movie or close to, "The English Patient" was a 12 movie that was popular at the time -- and it called 13 attention to the testing that was being done by some 14 pesticide companies on the effects of their pesticides 15 on human subjects. 16 The tests were mostly conducted at a facility 17 in the United Kingdom, and the environmental working 18 group charged that this was an attempt to circumvent or 19 undercut the provisions of the newly passed Food 20 Quality Protection Act by eliminating what was then and 21 continues to be EPA's normal practice in risk 22 assessment of using a tenfold uncertainty factor or 23 safety factor in extrapolating from animal data to 24 human protections. 25 In response to the environmental working PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 174 1 group's report, EPA acknowledged its own concern. We 2 said, yep, there are some questions here, some serious, 3 important, scientific, ethical questions and we need to 4 look more deeply and closely at it. 5 We convened a blue ribbon advisory committee 6 jointly with two groups in EPA that advise us, the 7 Scientific Advisory Panel and the Science Advisory 8 Board and they took several years to meet about and 9 discuss the questions involving this type of testing. 10 They had representatives from the human 11 research community, the bioethicists, toxicologists, a 12 very broad group of disciplines and a very respected 13 group of people who are on the committee. 14 They met several times in public meetings, 15 took comments, and developed and issued a report in 16 September of 2000. 17 The report has both areas of consensus and 18 areas of disagreement. In particular the committee 19 divided on the acceptability of no adverse -- no 20 observed adverse effect level studies or what we call 21 NOAEL studies. One group, a minority group, said that 22 these studies in humans with human subjects should not 23 be accepted under any circumstances. The other group 24 identified a set of criteria that they suggested EPA 25 consider. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 175 1 After mulling it over and changing 2 administrations and mulling it over some more and then 3 mulling it over some more, we decided that this really 4 was an area that continued to be controversial, that 5 continued to be one where at least with respect to this 6 critical issue of NOAEL studies we felt we wanted more 7 guidance. And so in December of this year -- of last 8 year, excuse me, we asked the National Academy of 9 Sciences if they would be willing to provide us advice 10 on the subject. And they have, in fact, agreed to do 11 so and we'll be convening and advisory committee with 12 composition we anticipate from some of the same 13 disciplines as our earlier group and will work with us 14 and work with each other to develop advice on how to 15 deal with this particular category of pesticides. 16 We have asked them to look at a variety of 17 issues, not exclusively ethical issues, although they 18 are certainly included, but also scientific issues, 19 what factors should we consider in determining whether 20 to accept or rely on human studies performed by third 21 parties. Are there boundaries, clear lines that could 22 be drawn between those studies that are acceptable, 23 both ethically and scientifically or studies that can 24 be clearly put aside because they don't meet standards 25 of scientific and ethical acceptability. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 176 1 If you can't draw clear cut lines and say 2 this is okay and this is not, what factors, what kinds 3 of factors ought to enter into that consideration. 4 What kind of documentation do we need to have in order 5 to be able to assure ourselves that we have a basis for 6 making those kinds judgments. Are there existing 7 standards, either in the Common Rule or in the 8 Declaration of Helsinki or some other source that we 9 could turn to and say, these represent the standards 10 that should be applied in terms of decision-making. 11 Are there different standards for different 12 kinds of tests? Do studies that are designed to 13 quantify no observed adverse effect levels, should they 14 be treated differently from other types of human 15 studies that have been identified? 16 So we have issued -- we have asked the 17 Academy to undertake this endeavor for us and they have 18 agreed. We are in the process of working out with them 19 the schedule and exact process that they will be 20 following. We have asked them to make sure as they do 21 their work that there is ample opportunity for the 22 public to make their views known. We will encourage 23 the Academy to have public meetings where they can hear 24 directly from people who have an interest in these 25 issues. They will ask them to allow the public to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 177 1 submit written comments as well. And at the end of it 2 we hope to get some advice that we can use and go ahead 3 and deal with this issue. 4 At the same time that we announced our 5 intention to talk with the Academy about this, we also 6 said that we were going to apply an interim policy 7 which essentially is that we will not look at and use 8 in our regulatory decision-making any studies conducted 9 by third parties that involve intentional dosing of 10 human subjects for the purpose of quantifying a toxic 11 end point. That policy statement that we announced in 12 December is a continuation of an approach that we had 13 announced several years earlier in connection with our 14 statements about the study, the report issued by the 15 environmental working group. 16 One difference in what we said in December is 17 that this policy approach, this interim policy applies 18 not just to pesticides, but to all areas of EPA's 19 regulatory decision-making. As I'm sure you'll hear 20 more about later, this subject is considerably 21 controversial and in mid-February the interim policy 22 was challenged by members of the pesticide industry who 23 argued that it was an illegal rule and have asked the 24 U.S. Court of Appeals for the District of Columbia to 25 set aside that policy statement and to order EPA to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 178 1 consider the results of this kind of study. 2 At present, the Court has not ruled on the 3 various motions that the parties have made and so we 4 continue that interim policy in effect. 5 I hope with this background that you have at 6 least come to the conclusion that there are lots of 7 subtleties and nuances in trying to figure out how to 8 approach this area. I do want to point to one thing 9 that I think is different from what might be your 10 customary kind of approach to matters, and that is that 11 a lot of the human research that EPA -- well, not a 12 lot, but at least some of the human research that EPA 13 receives comes to our attention after the study is 14 completed. We are not, as I said, in the business of 15 requiring or encouraging testing and sometimes 16 companies will come to us and ask us about a study 17 design, but more often studies will be started by a 18 company and completed before EPA is aware that they're 19 in the works. 20 And so the decision that we're facing then 21 is, not how to design the study in such a way that it 22 is designed to protect human research -- research with 23 human subjects -- but rather, what should we do after 24 the fact? What should our approach be in those 25 circumstances? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 179 1 I guess I will stop there and let you all ask 2 questions. Thank you. 3 CHAIRPERSON MARSHALL: Thank you. Thank you 4 very much. That was a very nice overview and sort of 5 statement of the problem and the issue. It really does 6 raise the forbidden knowledge question. That's the 7 issue on the table. And I have to say that when you 8 used the third party language that I saw the collective 9 shiver that went around the table of committee members. 10 But this is studies collected by third parties. So 11 have no fear, that other issue is at rest. 12 Let me open the floor up to questions first 13 by the committee. I have Abbey, I have Sandy, I have 14 Adil. Abbey. 15 MS. MEYERS: I have two questions. First, 16 why hasn't EPA issued regulations for implementation of 17 the Common Rule? 18 MR. JORDAN: EPA has issued regulations 19 implementing the Common Rule. And as I said, we do 20 follow the Common Rule for studies that we sponsor or 21 conduct. 22 MS. MEYERS: And just in what you sponsor. 23 But, for example, FDA doesn't develop drugs, but they 24 regulate the industry that develops drugs and so they 25 have regulatories that require all studies to be done PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 180 1 in a certain way in order to be acceptable when they're 2 submitted. And EPA hasn't done that? 3 MR. JORDAN: No, we have not. 4 MS. MEYERS: Well, that seems to be a big 5 problem. The other question that I have is, in the 6 literature that we were given it seems that small 7 numbers of people, you know, a dozen or two dozen or 8 whatever have been studied for a short period of time. 9 And a lot of the public's fear about pesticides comes 10 from the fear that long-term exposure or exposure to 11 children in the food is causing all kinds of problems, 12 birth defects in women, or children with hyperactivity 13 or whatever. And so the fear of the public seems to me 14 that there is something that EPA can do to at least 15 require, if you're going to accept human studies, to 16 require that these things be long-term exposure before 17 they're acceptable. 18 MR. JORDAN: There are a couple of points. 19 Human studies database that we at EPA have include 20 studies that are in some cases more than ten or even 20 21 years old and other studies that have been conducted 22 fairly recently. The more recently conducted studies 23 tend to have much larger numbers of participants, I 24 think usually over 50. More recent ones, and I'm not 25 absolutely sure I've got the numbers right, but I think PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 181 1 the smallest number of participants was 44 and at 2 different dose levels. 3 In terms of the study design, and the 4 chemicals study, most of them have been, as you 5 correctly point out, short-term studies involving 6 either a single exposure or sometimes exposure over the 7 course of a few days or maybe weeks, but seldom longer 8 than a month. The reason for that, I think, is that 9 the chemicals of concern have been ones which in animal 10 studies have displayed short-term effects, generally 11 colon estrace inhibition and the intent of the studies 12 is to understand better the human dose response 13 relationship. 14 My impression is that in order to get a study 15 over a lifetime of exposure would -- or even a 16 substantial part of a lifetime would be prohibitively 17 expensive and we wouldn't see any of that sort of 18 study. We do get and have been getting our 19 epidemiological data from a variety of sources 20 including a national agricultural study that has 21 followed people for close to two decades and that's 22 beginning to provide some very useful information in 23 terms of long-term effects. 24 MS. MEYERS: Is it negative? 25 MR. JORDAN: For the results that are coming PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 182 1 up, the epidemiological data are mostly negative, but 2 some of them are suggestive and pointing in a positive 3 direction. I don't want to talk about anything until 4 all the numbers are crunched and all the questions are 5 asked about confounding factors. 6 CHAIRPERSON MARSHALL: I have Sandy, then 7 Adil, then Bob, then Margaret. 8 MR. CORTASI: Could I interject a comment 9 here, please? 10 CHAIRPERSON MARSHALL: Yes. 11 MR. CORTASI: EPA -- 12 CHAIRPERSON MARSHALL: After you first tell 13 us who you are. 14 MR. CORTASI: Roger Cortasi at EPA. 15 CHAIRPERSON MARSHALL: Thanks, Roger. 16 MR. CORTASI: EPA's approval of studies 17 involving human subjects on the basis of chronic 18 studies, we basically do not approve them if it 19 involves any deliberate dosing of a human being. I'm 20 not saying that somebody couldn't come up and find a 21 case where we would, but so far we have not done and 22 our order prescribing how we will handle human studies 23 basically says there's a presumption that any such 24 study will not be approved unless you can think of some 25 pretty good arguments that we haven't thought of. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 183 1 CHAIRPERSON MARSHALL: Thank you, Roger. 2 Sandy. 3 DR. CHODOSH: I guess I have a few concerns. 4 One, you mentioned that when the third party industry 5 actually does the studies, you don't preapprove the 6 protocols, but you do expect them to have that the 7 subjects be fully informed and something about 8 scientific merit, nothing about IRB approval, and none 9 of the studies that I have seen reported in these 10 papers that we were given suggests that there was any 11 scientific validity considering the numbers of subjects 12 involved and there's an implication in these papers, I 13 know it sounds different from what you're saying, that 14 this data in fact was used to decrease the risk element 15 of quote, "the factors of ten." If that were the case 16 and that was totally unethical, that's number one, and 17 so I don't understand, it said this -- Dr. Cortasi said 18 that the EPA did not accept any of that data in 19 determining the risk level, but these papers suggest 20 differently. What's the truth? 21 MR. JORDAN: I think that the papers do have 22 -- the papers in the binder do have some errors in 23 them. Since -- let me make sure I get this right -- 24 since 1998, which is the time period that I think the 25 paper refers to, EPA has not relied on any human study PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 184 1 to reduce the uncertainty factor that I'm aware of. I 2 believe I would know about them if we had, in terms of 3 pesticides certainly. An I can't speak to other parts 4 of the agency. 5 The question of how many human subjects need 6 to have been included in a study in order to have 7 scientific validity is one of the scientific issues 8 that we hope to get advice on. The numbers of animals 9 in animal studies are generally considerably larger 10 than the numbers in these human studies, but the 11 question of how many is enough is one of the questions 12 to which we don't have an answer at this point. 13 CHAIRPERSON MARSHALL: Adil. 14 DR. SHAMOO: Thank you. This is going to 15 sound strange, but I'm going to come to the defense of 16 EPA. This is not an EPA problem. Really, it is not. 17 And the reason is, nearly half of research 18 with human subjects is not regulated. The industry can 19 do that with or without your approval. They care less. 20 As a matter of fact, they could do this research to 21 defend themselves from future liability from individual 22 law suits. So the problem is really for this committee 23 and for OHRP and for who else is involved in human 24 research protections is to make this issue that we need 25 a national human research protection act similar. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 185 1 This research with EPA cannot be done on cats 2 and dogs since 1966 because they have to comply with 3 the Animal Welfare Act. So it's really not an EPA 4 problem. This is all irrelevant, what we are talking 5 about. All the questions to the EPA, EPA gets those 6 data after the fact. Industry can do whatever they 7 wish because it's not just industry, private 8 foundations, state institutions, anybody. Somebody in 9 his garage, they could do any kind of research as long 10 as it's not federally funded or FDA bound for drug 11 licensing. And that is really the problem. 12 We are discussing now really the tail rather 13 than the dog. Thank you. 14 CHAIRPERSON MARSHALL: Thanks, Adil. Bob. 15 DR. R. LEVINE: Tu. I have two questions. 16 The first one, well, first a comment and then a 17 question. When you said you were looking around for 18 models you could draw on to develop your human subjects 19 protection policy, you mentioned Nuremberg and 20 Helsinki. I think you have to be careful about that 21 because Helsinki was specifically developed to over 22 biomedical research which it does not do very well. 23 But it certainly doesn't cover any other type of 24 research. So some of the particular articles of 25 Helsinki would be quite irrelevant to anything outside PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 186 1 biomedical research. 2 Nuremberg might be a closer fit. Although 3 we've come a long way since the Nuremberg standards 4 were articulated, but at least Nuremberg among the 5 examples they had to consider at the tribunals were 6 evaluation of the pesticides and poisons. But, still, 7 in the 50 plus years since Nuremberg, understandings of 8 research have changed. 9 Now, the question that I wanted to bring up 10 is, if I heard you correctly, what I heard was that 11 there were no standards based upon human safety by EPA 12 that would control the entry into the marketplace of 13 new pesticides. I said, if I heard you correctly. 14 MR. JORDAN: Okay. 15 DR. R. LEVINE: I wonder if there are any 16 safety standards for entry of these things into the 17 marketplace? Thank you. 18 MR. JORDAN: Okay. I surely hope I did not 19 leave that impression with others, and if so I 20 apologize. The laws under which we make our pre-market 21 approval decisions clearly articulate safety standards. 22 In the case of the Food, Drug and Cosmetic Act it is a 23 reasonable certainty of no harm. That's a collection 24 of words that doesn't necessarily entail any specific 25 standard, but through years of application first within PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 187 1 the Food and Drug Administration context and more 2 recently building on what we have been doing at EPA, 3 and now under the new law it has a very, I would say, 4 well-understood and pretty fully fleshed out 5 understanding and application within the Agency. 6 In general terms I'll give you a sort of 7 thumbnail sketch of the way we do our risk assessment 8 and use that as an explanation of the safety standard. 9 In terms of substances that display evidence 10 of being potential human carcinogens based on animal 11 data and other relevant information and structural 12 activity and epidemiological information, reasonable 13 certainty of no harm means using conservative models, 14 the anticipated exposure is less than one in a million 15 lifetime probability increase in cancer risk that in 16 given the conservative assumptions built into our 17 exposure assessments and so forth is regarded by our 18 scientists as biologically zero. 19 In the context of substances which are not 20 presumed -- which are presumed to have a threshold, we 21 apply -- we pick the no-observed adverse effect level 22 in animal data which is the most sensitive endpoint of 23 all of the different studies that have been performed. 24 In other words, if one were exposed to the pesticide, 25 what's the first effect that would be seen in terms of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 188 1 exposure levels? And from that level we apply or 2 extrapolate an acceptable daily intake, sometimes 3 called a "reference dose," in EPA's terms, that is 4 typically 100 to 1000 times lower than the most 5 sensitive animal NOAEL. 6 And in judging against those hazard 7 benchmarks what we need -- what we do at EPA is to make 8 sure that the exposure that people get through the food 9 they eat, the water we drink, the exposure that we get 10 in the course of living places where pesticides may be 11 used that all of that exposure is less than the safety 12 benchmark. 13 So those are the standards that we apply in 14 judging whether or not to let a product on the market, 15 whether or not to set a tolerance. 16 CHAIRPERSON MARSHALL: I have Margaret, Mary 17 Kay, and Judy, and then I'm going to open the floor up 18 for our ex-officio and public members. We are running 19 a bit behind and imposing on Mr. Jordan's time. So, 20 Margaret. 21 MS. BORWHAT: I just want you to clarify, if 22 you would, that right now under interim guidance you 23 are not relying upon any deliberate dosage of human 24 subject, and does that include, you know, a combination 25 of any information from this type of study mixed with PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 189 1 any of the animal models and information from the 2 animals. 3 And, secondly, I'd like to know if there's a 4 reason that you could state why the studies that were 5 mentioned in the article were conducted in England? 6 And, third, I'd like to know if you have any 7 data on profound chemical sensitivity in humans? In 8 other words, you're looking to see whether there's a 9 rise or an increase in the number of people who are 10 having profound sensitivity? 11 And, finally, I might suggest as a model your 12 mentioning Helsinki that perhaps something as simple as 13 "do no harm" might suffice. 14 MR. JORDAN: Okay. If I miss any of those, 15 please don't hesitate to ask again. 16 First question had to do with combinations of 17 animal data and human studies. To my knowledge we 18 haven't received any. I, therefore, don't know exactly 19 how the policy would apply. But I would think that 20 sort of methodologically one would construct the 21 studies separately with animals and with humans and we 22 would, under our interim policy look at the animal data 23 and the human intentional dosing of humans for 24 establishing a NOAEL we would not look at. 25 MS. BORWHAT: If I could just comment. There PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 190 1 really is no way that you're discouraging in any real 2 fashion companies bringing forward this information. 3 MR. JORDAN: As others have said, we cannot 4 prohibit them from conducting those studies. But we 5 think it's a very strong signal to say we're not going 6 to look at them. 7 You asked a second question about chemical 8 sensitivity. I do not know of any data. Others who 9 are here from EPA may be familiar with information I'm 10 unaware of, about changes -- in the incidence of 11 chemical sensitivity in the human population. 12 Certainly through anecdotally in my years in EPA, what 13 I've seen is more expressions by people of concern 14 about that. But whether that is simply improvement on 15 the part of medical science and being able to recognize 16 something that was there before, or whether it's in 17 increased incidence, I just don't know. 18 I'm missing one. There was a third question. 19 MS. BORWHAT: England. 20 MR. JORDAN: England. I don't know why these 21 studies were done in England. I simply don't know. 22 CHAIRPERSON MARSHALL: Thank you. Mary Kay. 23 DR. PELIAS: Thank you, Mary Faith. I have a 24 rather direct question that doesn't have anything to do 25 with or has very little to do with adults who are PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 191 1 exposed to pesticides. I wonder what your protocols 2 provide for in the way of rigorous observations having 3 to do with teratogenic effects and mutagenic effects 4 that would show up in the next generation, but not 5 necessarily in this generation? 6 MR. JORDAN: We are directed by the Food 7 Quality Protection Act to pay particular attention to 8 potential risks to infants and children. And as part 9 of that we are directed to apply an additional 10 uncertainty factor of ten. So when I was answering the 11 question earlier about are there safety standards, I 12 said our uncertainty factors range from 100 to 1,000. 13 That range is attributable to the FQPA provision 14 directing us to use an additional uncertainty factor of 15 10. Unless we have reliable data that we believe 16 supports using some different factor from ten. 17 In terms of assessing that risk, the standard 18 data requirements include teratogenicity studies in two 19 different species as well as a two-generation 20 reproductive toxicity study. And we have increasingly 21 been requiring a developmental neurotoxicity study and 22 we generally require mutagenicity studies for point 23 mutations, chromosomal aberrations and a sort of catch- 24 all category that I'm not sure I technically qualified 25 or described. It includes things like cystachromatid PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 1 92 1 [ph] exchange and other assays that evaluate the 2 potential of a chemical to interrupt the genetic 3 replication. 4 DR. PELIAS: Just one further question, are 5 these all in mammalian models? 6 MR. JORDAN: The teratogenicity studies and 7 the reproductive toxicity studies and the developmental 8 neurotoxicities are all in mammalian species. We do 9 have wildlife studies in both fish and aquatic 10 invertebrate and bird. Thank you. 11 And the mammalian -- the mutagenicity studies 12 are in a range of systems some of which are mammalian 13 systems and others of which are not. 14 CHAIRPERSON MARSHALL: Judy, and then we'll 15 open the floor. 16 DR. SIEGEL: I think my question may have 17 been dealt with. I also, from reading documents was 18 under the impression that although you didn't ask for 19 these studies they did, in some cases affect 20 regulation. And so I guess my comment would be the 21 same as Margaret's at this point. Is there -- you say 22 you won't look at it, but that doesn't discourage them 23 being done. I think that that's clear which may not be 24 your issue, but may. 25 And then, again, the other questions that I PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 193 1 was going to bring up really have to do with -- which I 2 think probably aren't appropriate -- when you do start 3 using these kinds of studies, what is the 4 predictability and the generalizability of these kinds 5 of results. But if you're not using it, that's not the 6 issue. I think more the issue is, are we actually 7 talking about regulating and non-regulated industry? 8 MR. JORDAN: To be fair, I want to say that 9 prior to 1998, in some cases EPA has used human studies 10 as the basis for regulatory decisions, since 1998 we 11 have not done so. I believe the article that I read 12 indicated that after '98 we had done so. And that's 13 not correct. 14 CHAIRPERSON MARSHALL: Thank you. 15 Any of our ex-officio or public members have 16 questions at this point? Oh, yes, Sandy. 17 Please step up to the mikes if you would like 18 for us to hear from you. 19 DR. CHODOSH: So far we have been hearing 20 about testing individual pesticides, but it's pretty 21 well-known now that we are being bombarded by a 22 multiplicity of all kinds of chemicals in our drinking 23 water, et cetera, et cetera. Have any of the studies 24 been required to look at the effects of a pesticide or 25 a new agent in relationship to others that are now in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 194 1 our environment? 2 MR. JORDAN: Generally speaking, no. There 3 are research academic work being done by researchers 4 which do look at chemical substances in combination. 5 And whenever we are aware of such data we will 6 certainly look at it. One thing though that does speak 7 to the concern that you raise it that the Food Quality 8 Protection Act directs EPA to, when we're regulating 9 pesticides, to take into account substances that share 10 a common mechanism of toxicity. And, in fact, we have 11 just completed in this past December a cumulative risk 12 assessment looking at 39 different organophosphate 13 substances together where all of those chemical affect 14 colon estrace inhibition, cause colon estrace 15 inhibition and we have prepared an assessment that 16 takes into account the exposure that people get as a 17 consequence of eating food and potentially consuming 18 residues of all of those different substances as well 19 as the residues that might be present in drinking 20 water, as well as the residues that we might encounter 21 on golf courses, or as a result of spraying a cockroach 22 control agent or something like that. 23 It's something that, to summarize, took us 24 3,000 pages. And the charts and graphs and data sets 25 behind it are, you know, sort of an order of magnitude PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 195 1 almost greater than that. It's something that took 2 years to produce and we're pretty proud of it. And 3 it's a start. 4 CHAIRPERSON MARSHALL: Elliot. 5 DR. DORFF: Given the amount of food that 6 comes into that is country from abroad, does EPA deal 7 at all with pesticides on food that comes from abroad? 8 MR. JORDAN: We do. The food that is 9 imported in the United States and the food that is 10 grown domestically are subject to the same safety 11 standards. The tolerances that EPA established apply 12 equally to both imports and domestically grown food. 13 The Food and Drug Administration maintains a 14 sampling program. It's weighted more heavily toward 15 sampling imports than it is domestic foods. By and 16 large both domestic and imported food have a relatively 17 low violation rate, although imports are somewhat 18 higher than domestic food. And then that is 19 supplemented with a monitoring program that the 20 Department of Agriculture, U.S. Department of 21 Agriculture maintains that looks both at domestic and 22 imported foods. 23 CHAIRPERSON MARSHALL: Mark. 24 MR. BARNES: What occurs to me is that there 25 may be a category of sort of human subjects type PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 196 1 research that sort of maybe is not contemplated by the 2 post-1998 practice. And that is, if I were -- I mean, 3 just thinking about what I've learned today in looking 4 at this and listening to you talk. 5 If I were a pesticide company, and I knew 6 that EPA was not going to use the deliberate dosage 7 studies in approval, then what I would probably do is I 8 would go to a developing country and I welcome simply 9 give out my pesticide to be used there and then as 10 people wanted, and since it was free, I presume people 11 would use it, and then I would do population-based 12 studies to see what the toxicity would be based on the 13 use that was reported. And then I would write that up 14 and I would give it to you because I would say that was 15 not deliberate dosing. And so my question is, would -- 16 I mean, that kind of study would you -- how would you 17 treat that? And I don't mean to be pejorative about 18 the pesticide industry, I'm just trying to -- I mean, 19 I'm a layer, so I think of where the loopholes are. So 20 -- 21 [Laughter.] 22 MR. JORDAN: I don't know. It certainly 23 raises a lot of troubling questions. I am happy to say 24 that we haven't had that circumstance arise, and for a 25 variety of reasons I hope we don't. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 197 1 CHAIRPERSON MARSHALL: I have a question, and 2 that is, you may not know the answer at this point, but 3 do you have a sense of time frame for the National 4 Academy Committee's work? 5 MR. JORDAN: Preliminary discussions 6 indicated they would be done sometime summer of next 7 year and we asked if they could move somewhat more 8 expeditiously. And we are in the course of discussing 9 that further with them. 10 CHAIRPERSON MARSHALL: Thank you. 11 Any further questions? 12 [No response.] 13 CHAIRPERSON MARSHALL: Then we will move on 14 to our panel and Mr. Jordan, thank you so much for 15 being here. It was just a wonderful presentation. 16 Really appreciate it. 17 [Applause.] 18 CHAIRPERSON MARSHALL: So I'm going to ask 19 the members of the panel if they would just come 20 forward and we're going to shuffle some chairs and 21 proceed right along. 22 [Pause.] 23 CHAIRPERSON MARSHALL: So thank you, panel 24 members. We're going to move right along. We've 25 tried to provide balance in terms of overview and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 198 1 perspective and I think we have a wonderful panel. 2 We will begin with Richard Wiles how is 3 Senior Vice President of the Environmental Working 4 Group. He will for example followed by Howard Sandler 5 who is President of Sandler Occupational Medicine 6 Associates and I think not directly associated with 7 CropLife America, I think that's -- yes. 8 DR. SANDLER: No relationship with them. 9 CHAIRPERSON MARSHALL: Right. Thank you. So 10 that is an error of ours. 11 And then Russell Katz who is director of 12 Neuropharmacologic Drugs Products, Center for Drug 13 Evaluation and Research the Food and Drug 14 Administration. 15 So, gentlemen, thank you all for being here 16 with us today. And, Mr. Wiles, you're up. 17 MR. WILES: Thank you, Mary Faith. 18 I'll try to make this a little bit direct and 19 maybe exciting and hopefully I won't be too unethical 20 or make anybody too mad, but this may be my last 21 chance. It's my first chance in front of one of these 22 kinds of committees, so I want to get our view out 23 there clearly. I want to talk about human subject 24 research in reality as opposed to sort of the theory of 25 human subject research which is where we tend to get PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 199 1 bogged down in these arguments with EPA. 2 The distinction is critical because EWG and 3 other environmental groups could potentially support 4 some limited types of human studies -- emphasis on 5 "limited" -- with pollutants and pesticides in some 6 sort of a fantasy world that doesn't exit. But 7 unfortunately, we don't live in that world and since 8 we're stuck in the real world, we are opposed to all 9 direct dosing studies on humans for all pollutants and 10 pesticides. 11 Having said that, we are very much in favor 12 of what you would call "biomonitoring studies"; 13 monitoring the population for their exposure to these 14 things on the market, passive dosimetry for workers and 15 those kind of things. Obviously we're not opposed to 16 that. We are opposed to direct dosing. 17 I'm going to talk about pesticides, but I 18 also will include chemicals and pollutants generally in 19 the argument as well. Pesticides, pollutants and 20 chemicals have to be considered in a fundamentally 21 different light than medicines and other substances 22 where human subject research is involved for a number 23 of reasons. 24 First, these compounds are either designed to 25 be toxic as with pesticides or they are the unwanted PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 200 1 byproducts of industrial processes. They do not 2 provide direct benefits to the individuals who are 3 subject to the trials, to the studies that they're in. 4 And, importantly, as Bill Jordan mentioned, 5 but I'm going to say it again, human studies are not 6 required to get a pesticide on the market, or to get an 7 industrial chemical on the market. They are not 8 required and they never have been required. They've 9 been thrown over the transom, but they have not been 10 required. 11 They principally have been submitted in an 12 effort to erode safety margins that have been attached 13 to animal studies, and I'll get to that later. 14 At the same time, unlike medicines, for 15 example, a medicine, say that hasn't been approved for 16 the market, there is a widespread ongoing human 17 exposure to all these chemicals which we think makes 18 the case for biomonitoring as opposed to more direct 19 dosing studies. 20 There are estimates that we're all exposed to 21 about 500 pesticides and industrial chemicals in our 22 bodies today. We don't know the number or the levels 23 of the health effects of these compounds on us mostly 24 because the industry that wants to do these direct 25 dosing studies has actively worked to make sure that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 201 1 tests to monitor the population exposure to the 2 chemicals currently on the market are not done. They 3 are not required by law and they're not volunteering to 4 do these studies. 5 Now some background. Bill gave a little bit 6 on the FQPA, Food Quality and Protection Act, and the 7 new standards they put in place to protect children. 8 The critical point here is that it required 9 an additional tenfold margin of safety attached to the 10 animal NOAEL unless the agency had explicit data to 11 support not doing that. The agency has not 12 consistently followed the law in our view on that. But 13 they have applied the tenfold sometimes and other times 14 they have not applied the tenfold. But in any event, 15 the industry saw this as potentially a big problem. 16 In 1998, we investigated this issue and 17 produced a report called "The English Patients" -- 18 which you seen at least a part of -- and came to three 19 basic conclusions: One, that EPA was routinely using 20 human data to establish safety standards at that time. 21 That's 1998. 22 Since then Bill, I presume, is correct, or 23 I'll have to take his word for it, I won't challenge 24 him today as to whether or not they've set standards 25 based on human data. We know that we've seen internal PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 202 1 memos since '98 where staff had recommended that safety 2 margins be rolled back based on human data. Whether or 3 not that translated into a final regulation I'll have 4 to take Bill's word for it. 5 EPA had no policy governing the ethics or 6 scientific protocols of studies involving human 7 subjects that were not -- that were conducted 8 independently and submitted to the Agency. And that's 9 the problem they still face today is that these 10 contractor studies are sort of out there with limited 11 control. 12 But most importantly, the industry had 13 developed an explicit plan to increase the volume of 14 human tests, the number of human studies they were 15 going to do as a strategy to avoid stricter regulation 16 under the Food Quality Protection Act. But I'm not 17 going to ask you to believe me when I say that. I will 18 read you from this document which is prepared for the 19 chemical industry, the pesticide industry, in 20 particular, and they say, they're talking about 21 implementing strategies to implement the Food Quality 22 Protection Act: 23 "Registrants" -- that's manufacturers of 24 pesticides -- "will find it increasingly 25 undesirable to rely on endpoints derived from PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 203 1 animal data since this customarily requires 2 the application of a tenfold uncertainty 3 factor to account for interspecies variation. 4 For this reason there probably will be an 5 increased reliance by registrants on data 6 from human studies on acute or short-term 7 toxicity of organophosphates in this case 8 that could avoid the need for that tenfold 9 uncertainty factor from interspecies 10 extrapolation." 11 That may not be enough to convince you, but 12 here is Jay Vroom, the top lobbyist, head of the 13 Agricultural -- oh, wait, it's not called that, it's 14 called Croplife America, and he says in the Washington 15 Post in November of last year, "Testing pesticides in 16 people," Vroom said, "allows companies to show the 17 agency that humans can safely receive higher doses." 18 So it's clear why they're doing this. 19 We look at this for human testing in terms of 20 sort of an ethical hierarchy. The question for us is 21 what are the most unethical practices in place and what 22 do we need to do to fix them, and overall what do we 23 need to do and what's the most pressing need in terms 24 of pesticide regulation to improve pesticide and 25 chemical safety? So I've identified three that I'll PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 204 1 throw out for you today, three particularly unethical 2 situations. 3 One, it should be for the chemical industry 4 as a whole where they basically have not tested or 5 there's very haphazard testing, no requirements for 6 thorough health and safety testing for commercial 7 chemicals, not pesticides, before they go on the 8 market. So we walk around with them in our bodies, but 9 they're not very well tested. That doesn't apply to 10 pesticides which are well tested by the same companies. 11 For the pesticide industry, the biggest -- 12 one of the biggest ethical concerns with us is their 13 resistance to this additional tenfold safety factor 14 required by law, the Food Quality Protection Act, and 15 in particular its opposition to the -- its explicit use 16 of human studies and the strategies to subvert that 17 extra tenfold factor. 18 And the broader thing that gets back to 19 biomonitoring is the fact that the pesticide and 20 chemical industry is exposing all of us on a daily 21 basis to pesticides and has refused systematically to 22 monitor the population in a statistically valid way to 23 find out where those exposures are, or if there's any 24 reason to be concerned. And they have specifically not 25 been very cooperative with the Centers for Disease PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 205 1 Control, or let's just put it this way, I wouldn't say 2 they haven't been cooperative, they don't volunteer a 3 lot. They're probably cooperative when asked, but 4 they're not out there volunteering to give the 5 analytical methods for some of these pretty complicated 6 pesticides to the CDC so that they can look in the 7 blood samples and see if they're there or not. So we 8 don't know. 9 Instead, we want to do direct dosing studies. 10 So in order to sanction a practice like human 11 subject research, we would argue that you need to show 12 that the human testing will directly address the 13 ethical shortcoming or the public health problem that's 14 caused by the industry in the first place. If we're 15 going to do these studies, they ought to be advancing 16 some public health goal which we don't support the 17 studies, but at least they ought to make that 18 justification. There is no way they can say that they 19 would do that. Remember, this is not about finding 20 medicines to cure a disease. I mean, it's not about 21 improving the ethics or the practice of the studies, 22 and it's not about getting the pesticide on the market. 23 It's specifically about undercutting the safety 24 margins. 25 So let's talk a little bit about the science. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 206 1 Our position basically is that these human studies are 2 bad science and bad science is inherently unethical. 3 First, there's no protocols for the conduct 4 of these studies which is pretty outrageous considering 5 that there are probably more than 100 studies required 6 to put a pesticide on the market and the protocols for 7 these animal studies have been peer reviewed and 8 publicly reviewed ad nauseam. But when it comes to 9 human studies, there are no protocols at all, or let's 10 just say that they're ad hoc. You can't find them 11 anywhere if you went to look for them as a member of 12 the public. 13 Second is the sample size issue that was 14 touched on earlier. A lot of these studies had -- one 15 of my favorites was the human study on prisoners at the 16 Clinton Correctional Facility in Albany, New York that 17 was done in 1972 for Dow Chemical. That study had 16 18 people, four controls, four per dose group. It 19 supported the safety standard for a chemical called 20 cloroperofos [ph] it was the most widely used indoor -- 21 and it was the most widely used insecticide on the 22 market until it was finally banned -- based on dose 23 groups of four adult male prisoners extrapolated to the 24 entire U.S. population. 25 Now they've gotten these sample sizes up to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 207 1 maybe 20 or 30 per dose group which is still pretty 2 laughable if you're going to extrapolate out to a 3 population of 200-some-odd million that would be 4 exposed. 5 These small sample sizes have not stopped EPA 6 from looking at these studies. Now, they look at them 7 and they do sort of a dance where they don't pay 8 attention to it. They look at it, but they don't count 9 it. You know, and it's very difficult for us in the 10 absence of a clear prohibition or a clear set of 11 procedures to know what they're doing when they're 12 looking at them. That's why we do feel that if EPA did 13 have a formal policy that they would never, under any 14 circumstance use these that would stop industry from 15 doing them. 16 Third, federal pesticide law requires that 17 all pesticides in food be proven safe for the fetus and 18 infant. That is the clear requirement of the law. 19 Human studies on adults don't produce data 20 that's valid to make a conclusion about the safety of a 21 pesticide for the fetus or the infant. Indeed, they 22 may well provide you with an illusion of safety that 23 could lead to a dangerous relaxation of health 24 protections based on data derived from human adults in 25 small sample sizes than apply to the fetus. That's PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 208 1 exactly what industry is proposing. They wouldn't say 2 that, but got mad at me when I say that, but that's 3 what they're doing. 4 Realistically, the last of these two problems 5 with human studies can never be fixed which means that 6 the studies will forever be bad science and therefore 7 forever be unethical. Sample sizes of a thousand or 8 more in human studies, I hope, will never be reached. 9 And until you get to that size, you don't have any 10 power to extrapolate and find an effect that might 11 occur, let's say, in 1 percent of the population which 12 would actually be a pretty big effect. If it's less 13 than that, you've got to go even higher and you just -- 14 hopefully we won't have these human studies done with 2 15 or 3,000 people in them. And hopefully pesticides will 16 never be tested directly on the infants or the fetus. 17 Okay. And that is the federally required target 18 population that has to be protected by law. Okay. So 19 hopefully we won't be doing the test inappropriate for 20 that on people. 21 That's the science questions. The studies 22 are ethically challenged as well. 23 There is no application of the Common Rule to 24 research conducted by contractors and then submitted to 25 EPA. So virtually all human subject research on PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 209 1 pesticides is conducted by contractors and therefore 2 it's not subject to any rule. There is this 3 prohibition in FIFRA that says you have to basically be 4 a nice person and you can't have people in these tests 5 that aren't volunteering to be in there. But most 6 people that are in the studies that we've seen were 7 paid some pretty significant sums. So I don't know if 8 that's volunteering to be paid to be in the study of if 9 thy's volunteering. But in any event, I would argue, 10 or at least you should see that whether or not that 11 FIFRA requirement is as tough as the Common Rule. 12 Maybe it is, but I doubt it. 13 Second, there's no direct benefits to the 14 participants in pesticide and pollutant direct dosing 15 studies which violates a basic rule of all medical 16 human subject research. It's particularly ironic given 17 the fact that industry is refusing to conduct 18 statistically valid biomonitoring for their products in 19 the population, yet they want to dose people up in 20 these studies. 21 Third, human studies can only be used to 22 weaken health standards and to erode safety margins 23 that would be required by animal studies. 24 Now, that's sort of a sweeping statement. I 25 want to say it again because the industry won't like PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 210 1 this one either. But, I will argue that these studies, 2 in fact, only can be used to weaken standards. And 3 that you would have to find such an outrageous 4 difference in effect or toxicity in these studies that 5 would never happen, so there only could possibly be 6 done for the purpose of allowing more pesticide than 7 would be allowed by an animal study. And by that I 8 mean, remember that we have this tenfold margin of 9 safety and the three tens that go into FQPA, they give 10 you a thousandfold margin of safety. 11 If industry does a NOAEL study involving 12 human subjects, unless the data show a compound to be 13 more than ten times more toxic than the animal data the 14 standards won't be tightened because regulators in the 15 industry will argue that the current margins of safety 16 already account for that difference. So even though 17 the human study showed that it was more toxic, we'll 18 just leave the standards the same. 19 On the other hand, if a study, say of 30 20 people, shows less toxicity, EPA is not very likely to 21 -- oh, EPA is, excuse me, all to eager to relax 22 standards. And I do have one piece of paper that sort 23 of contradicts what Bill said, and this is from 1999, 24 where the agency concluded that they could apply a 25 threefold safety factor instead of a tenfold safety PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 211 1 factor based on plasma colon estrace inhibition in dogs 2 and humans from a 21-day human toxicity study. So this 3 may not have made it to regulation, but this was 1999. 4 And they are, in fact, using these very limited 5 studies to erode safety standards. So it's just 6 extremely unlikely, and I would argue, almost 7 impossible for human data to produce results that will 8 strengthen standards. 9 Now, industry will rebut this and say that 10 one-third of the studies that they have done have shown 11 that the pesticide was more toxic than the animal data 12 showed. And that may be true, but I'll challenge them 13 to find one case where that finding was then translated 14 into a tougher standard in the marketplace, a 15 restriction in the marketplace for those pesticides 16 where the tolerance and the legally allowable level was 17 actually reduced on the basis of those studies. There 18 may be a few, but I'd like to see them. 19 So, in summary, pesticide and chemical 20 companies are not doing these studies to get their 21 products on the market. They're not required. 22 They're doing them to erode safety margins, apply to 23 animal data, and they're doing them in a way that's 24 completely invalid scientifically using data on adults 25 to erode safety margins that are specifically targeted PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 212 1 protecting infants, fetus and children. 2 I could probably eliminate all this blather 3 here because I think you got the basic point. 4 Just to say one last thing is that we do 5 support biomonitoring. And I want to really emphasize 6 that. We would like to see comprehensive analysis 7 done, for example, on the blood that's gathered in the 8 Nhanes studies to really look and see what's detectable 9 in the human blood supply? What about the kids in that 10 study? Could we do real -- could we expand that survey 11 to include a better dietary profile and some exposure 12 estimates and then really check that blood for every 13 pesticide in the food supply and the chemicals likely 14 to be found there so we -- in those studies which have 15 3 or 4,000 people and are statistically designed to 16 inform agencies about decisions regarding nutrition and 17 other things, wouldn't it be a good place to look for 18 these chemicals to see what's actually ending up human 19 blood and urine and those kind of things. And so we 20 would definitely support that. 21 What we are opposed to is this direct dosing 22 of these studies, especially for the purpose of eroding 23 safety margins. 24 CHAIRPERSON MARSHALL: Thank you. I think 25 what I'm going to do is hold questions until each of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 213 1 the presenters has made his remarks. So thank you very 2 much. 3 Let's move on to Dr. Sandler. 4 DR. SANDLER: Thank you. I appreciate the 5 opportunity to be here today. 6 My name is Howard Sandler. I'm a physician. 7 I specialize in occupational and environmental 8 medicine. I served as a medical officer with the 9 National Institute for Occupational Safety and Health. 10 I've been an advisor to the U.S. EPA for their own 11 staff, safety and health. I've worked with OSHA and 12 NIOSH and the Consumer Product Safety Commission. I 13 spend a lot of my time designing and implementing and 14 looking at programs to keep workers and general 15 community residents safe and healthy. I work with 16 government. I work with industry, I work with labor. 17 I've worked with activist groups. 18 I'm from Long Island. We know something 19 about safety problems now. We also have a big problem 20 with mold in schools and some concerns about what is 21 risk and what isn't risk. Science is not inherently 22 bad. It's what you do, how you do science, and how you 23 use science that can be bad. 24 What types of rules do we make decisions on? 25 We made decisions using epidemiologic data. We make PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 214 1 it using animal data, we make it using in vitro studies 2 of all different types. Dr. Bruce Ames started a lot 3 of wonderful work for a lot of people around this table 4 and probably in other places. And all of this is good; 5 the more we know, the better off we are. 6 The first rule of medicine, what I was taught 7 at the University of Maryland was, do no harm. The 8 head of internal medicine who was a principal author on 9 rickettsial diseases, Ted Woodward, was a big influence 10 in my life. And, you know, he just said to me, said, 11 "Treat everybody like your mother and you'll be fine." 12 He never met my mother. 13 [Laughter.] 14 DR. SANDLER: But, you know, it's good -- and 15 by the way, she lives down here and I'm going to be in 16 big trouble because I cannot get the time to go see 17 her. 18 [Laughter.] 19 DR. SANDLER: But there's no good deed goes 20 unpunished; right? 21 There's nothing wrong with looking at 22 science. I think the question becomes, what health 23 endpoints are we really looking at. Are you going to 24 be doing reproductive effect studies on pregnant women 25 with pesticides? I don't think so, or at least I hope PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 215 1 not. Are you going to be dosing children? No, I don't 2 think so and I hope not. Certainly my son, Adam 3 Sandler, unfortunately not the real one, but -- 4 [Laughter.] 5 DR. SANDLER: -- I wouldn't want in a study. 6 Although he may end up doing his own dose response 7 studies on other things. 8 [Laughter.] 9 DR. SANDLER: The question really comes down 10 to, can you design studies that are looking at the 11 right health endpoints? For example, very limited 12 things such as colon estrace inhibition to see if there 13 really are changes in various types of groups. It may 14 be certain groups right now the studies are looking at 15 adult males that are "healthy." And we all know the 16 problems from the healthy worker effect in various 17 types of epidemiologic studies. 18 We use skin patches or testing frequently to 19 determine if people have problems. Chemical 20 sensitivity was mentioned here. And the bottom line is 21 that there are many practitioners out there who are 22 exposing people to chemicals in what we call chamber 23 challenges. 24 Dr. John Sellner did it, before he passed 25 away, and many times in Denver, and people down in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 216 1 Texas are doing these types of "challenges," 2 quote/unquote. Unfortunately many of those don't get 3 before human experimentation subject boards and other 4 entities that make sense. 5 I read through, and by the way, just so it's 6 clear why I'm here, I was asked by CropLife America to 7 review material and to provide an independent 8 assessment, hopefully underlining the word 9 "independent" and objective assessment of what I've 10 done through my career and what I think about this. 11 I think what you have to do is provide, you 12 know, the first thing, a good research effort with good 13 safeguards, make sure that there are appropriate 14 approval steps and people looking over shoulders, and 15 use the data when it makes sense. It should be part of 16 a certain process and maybe very, very focused and 17 specific. I don't think you should use human 18 experimentation to set LOAELs and NOAELs. You may end 19 up using it to refine a specific point within that 20 process after the animal studies certainly give you 21 some range of safety there. But I don't think it's 22 appropriate to use that to begin with and I don't think 23 it's legislatively a good idea, nor do I think it's 24 ever been proposed by anybody. 25 I guess the bottom line to what I'm saying is PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 217 1 that the report I read from the SAB, SAP working group 2 brought a lot of good common sense and I think a lot of 3 appropriate reasoning to this issue. I didn't find 4 fault. I read the minority aspect, excuse me, the 5 minority report aspect and certainly those concerns 6 need to be considered. But we do make those tradeoffs 7 all the time, keeping kids healthy and fit and fed is 8 an important thing. At the same time making sure that 9 you have the ability to keep them fed means a safe 10 productive food growth. 11 How do you do that in all populations is a 12 very important thing. 13 The National Academy of Science, I've served 14 on a committee there. They do good work. I'm 15 convinced that they will take the appropriate analysis 16 steps and do what's important and safeguard our 17 children. 18 Thank you. 19 CHAIRPERSON MARSHALL: Thank you very much. 20 I want to just interject that if there's anyone who has 21 joined us this afternoon who wasn't here this morning 22 and hasn't signed in to please do so during the break. 23 All right. Dr. Katz. 24 DR. KATZ: Thank you. I have a few slides. 25 Okay. The file is called Phase I. There's a few files PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 218 1 on there. 2 Let me just say it's a pleasure to be here. 3 In particular it's a great pleasure not to be a party 4 to this particular controversy. 5 [Laughter.] 6 DR. KATZ: It's a rare appearance by an FDA 7 person when we're not the center of a controversy or in 8 the cross hairs. So I appreciate that very much. 9 I've been asked to speak about how we think 10 about introducing potential toxins, that is to say, 11 investigational drugs into human beings. So I'm going 12 to talk about this issue in a generic way. It's 13 something that we deal with every day and so some folks 14 thought that it might be useful to bring that sort of 15 experience to bear on this particular issue. 16 So, if I could -- let me just also issue a 17 sort of a mini-disclaimer, I'll be giving you one 18 division director's point of view about these issues. 19 We have rules that are subject to interpretation so 20 everybody interprets them a little differently. I'm 21 going to give you sort of a general view of how we 22 interpret the rules in our division. 23 So if I could have the first side, please. 24 This is the first slide, but it doesn't 25 really say very much. So could I have the second PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 219 1 slide. 2 Okay. I think there's a basic premise that 3 underlies drug development, at least as I understand 4 and that would be something along the lines of, we view 5 all investigational drugs to be worthless, that is to 6 say, ineffective and dangerous until proven otherwise. 7 And so in some sense all proposed investigational drug 8 treatments can actually be considered potential toxins 9 and nothing else. 10 Obviously somebody thinks that these things 11 are going to be useful at some point, in particular the 12 pharmaceutical sponsor. But we know from experience 13 that lots of them don't make it either because they 14 just turn out not to work or not to be safe as we 15 understand the term. And so at the beginning certainly 16 we know nothing about human response to it either from 17 the point of view of effectiveness and safety, so we 18 really consider them all potential toxins and perhaps 19 nothing else at the outset of the introduction of these 20 things to people. 21 And so the onus is on the sponsor to 22 establish that the drug -- the potential drug is safe 23 and will be effective for the indication that they're 24 going for. 25 By the way, everything we deal with, all the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 220 1 regulations I'm going to talk about and certainly the 2 statute under which we work, and you've heard about the 3 Food, Drug and Cosmetic Act, these rules, these 4 regulations apply to investigational drugs and the drug 5 is defined in the Act as a substance that's designed to 6 affect the structure or the function of the body or 7 treat disease or diagnose. So somebody must think that 8 ultimately there is some use for these substances. 9 The next slide. 10 Okay. So I said that the sponsor has to 11 adduce evidence that the drug is safe and effective. 12 And, again, I'm going to be mostly talking about what 13 we call "phase one" experience, that is to say the 14 initial introduction of an investigational drug into 15 people. 16 So the first thing we require is relatively 17 detailed information about the chemistry and the 18 manufacturing. In other words, what is the product? Is 19 it what the sponsor says it is? In other words, if 20 it's supposed to be 100 milligrams, is it 100 21 milligrams. Of course, there's room for slight 22 variation, but is it in fact what the sponsor says it 23 is? Is it pretty much within fairly rigorous standards 24 the amount that they say it should be. 25 Every drug has impurities, indegradance, some PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 221 1 are built -- some occur as a result of the 2 manufacturing process and some are compounds that occur 3 over time as the product is left to stand, and there 4 are relatively strict rules about how much impurities 5 and degradance could be in a product. So if it reaches 6 a certain threshold we require animal studies to 7 investigate the safety of these things. 8 If a product is a parenteral, in particular, 9 if it's an injectable product, there are fairly strict 10 standards that are imposed to determine that the 11 product is sterile and stability. In other words, will 12 the product stay potent over time, particularly with 13 regard to how long the proposed human study is. Do 14 impurities and degradance increase over time? If they 15 do, that's a particular problem that needs to be 16 investigated further. But we want to know that at 17 least the product is stable for the period of time that 18 humans are to be exposed. And in particular, has it 19 been stable over the course of time that the animal 20 studies have been -- for the duration of the animal 21 studies that have been performed. 22 If I could have the next slide. 23 Okay. So there's the manufacturing 24 information that's very important. The other main type 25 of information that we require before drugs are PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 222 1 introduced in humans is animal testing. And there's a 2 general, I would say, overarching principal that is 3 applied to animal testing to determine whether or not 4 it's appropriate to support what the sponsor wants to 5 do in humans. And that is that usually two species, 6 rodents and non-rodents should receive greater 7 exposures than humans are supposed to receive for 8 longer durations, to be an appropriate route and 9 regimen. 10 That is to say, if humans are going to 11 receive an IV folie, animals should receive an IV 12 folie. If humans are going to receive a slow infusion, 13 animals should receive a slow infusion. And the idea 14 here is to stress the system in terms of the greater 15 exposure and the longer durations to see what exactly 16 the drug is capable of doing, at least in animals. 17 Animals aren't, of course, perfect models at all for 18 what happens to humans. But certainly we believe 19 they're the best we have. 20 And, again, the greater exposure, the longer 21 durations association make up for the fact that we 22 usually don't have very many animals in a particular 23 study. That varies according to species, but certainly 24 nowhere near as many animals as you ultimately will 25 have humans exposed. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 223 1 If I could have the next slide. All right. 2 Some more information about the animal studies. The 3 first on here speaks to probably the critical factor in 4 animal studies. That is to say there should always be 5 a linkage between the animal studies and the proposed 6 human studies. That means that in particular the 7 duration of animal studies should always be at least as 8 long as human studies. This is true up to a point. 9 Before a drug is ultimately approved, usually 10 we have several years' worth of data, at least in a few 11 patients. Certainly we have relatively long-term 12 exposure, assuming it's a drug to be administered 13 chronically. Animals don't have to be exposed for many 14 years for typical toxicity. It's usually six months in 15 a rodent and up to nine months or 12 months in a non- 16 rodent. So there are limits for the duration of 17 animals. But nonetheless, the animals, as drug 18 development is progressing and human exposure is 19 increasing, the animals need to always be one step 20 ahead of the humans, as it were. 21 Typically the initial proposed human studies 22 are single-dose studies, usually in healthy adult 23 volunteers, it depends on what the indication is, of 24 course, and to support those sorts of studies, the 25 typical animal studies are usually about two weeks. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 224 1 They can, by policy, be one single dose in animals if 2 only a single does is proposed in humans. But 3 invariably sponsors will submit studies in animals of 4 at least two weeks duration at the outset. Because 5 they're going to want to progress fairly rapidly into 6 multiple dose studies in humans. 7 So in addition there needs to be some, at 8 least beginning assessment of the genotoxic potential 9 in in vitro and in vivo studies with an eye towards 10 giving us an idea about potential carcinogenicity 11 although carcinogenicity studies in a formal way in 12 animals are usually completed fairly late in the 13 development of the drug. 14 If I could have the next slide. 15 More about animal studies. Again, just to 16 give you some general form, the animal studies usually 17 evaluate three doses or so-called low, middle, and high 18 dose. These doses are presumably determined on the 19 basis of dose finding studies in animals, what can they 20 tolerate, this sort of thing. There's a couple 21 purposes to the animal or a couple aspects of animal 22 studies that are critical. One is that a maximally 23 tolerated dose should be achieved in animals. 24 That is to say, again, under the heading of 25 stressing the system, we should give a dose to animals PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 225 1 beyond which they could not tolerate to really get a 2 sense of, again, what's tolerated. And these studies 3 all involve detailed histopathological examination of 4 essentially all tissues in the animals at all doses. 5 The idea here is to identify what, in fact, is the drug 6 capable of doing from a toxicity point of view, the 7 whole point being to give us an idea of at least where 8 to start to be looking in people. 9 It's also useful for a sponsor to detect no 10 effect level when you've heard something about that 11 already. And the "no effect" level could be defined in 12 many different ways. Either it could be a level below 13 which there is no minimal behavioral alterations or 14 histopathological alterations. Again, there is no 15 absolute rule for what is a no effect level or for that 16 matter what is a maximally tolerated level. 17 Sometimes you can't reach a maximally 18 tolerated level. The drug is so benign that animals 19 tolerate whatever you can give them. In that case, 20 usually what we would require a sponsor to do is to 21 give what's called the maximum feasible dose. That is 22 to say, sometimes you just can't get more in from a 23 physical point of view, the animal stomachs won't 24 tolerate it. Well, you can't create an intravenous 25 solution concentrated enough to get in as much as would PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 226 1 be necessary to induce toxicity. So that would be 2 called the maximum feasible dose and that, you can only 3 do what you can do. So that's, if not a maximally 4 tolerated dose, a maximal feasible does. 5 It's also very important to -- for us to know 6 that in fact for an oral drug that it actually is the 7 -- the animal is being exposed to it. It is possible 8 you could give lots of drug and the animal doesn't 9 absorb it through the intestine. So we like to have 10 some confirmation that in fact, as you increase the 11 dose of the drug, you actually are increasing the 12 exposure in the plasma or in the tissues. 13 If I could have the next slide. 14 We've head a lot about margins. We tend to 15 use a margin of about one-tenth to no effect level as a 16 starting dose in humans. But certainly there's no rule 17 that says human exposure can only go up to X if animal 18 exposure has only been X. You like there to be a 19 margin ultimately between what animals can tolerate and 20 where humans get in terms of total exposure. But if 21 humans can tolerate the drug with some exception which 22 I'll talk about a little later, if humans seem to be 23 tolerating the drug, you can push them slowly beyond 24 even what animals have been exposed to assuming animals 25 have reached the maximally tolerated or feasible dose. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 227 1 Okay. And here this is very important. It's 2 becoming much more important to us in recent years. As 3 soon as we can, we like to get detailed information 4 about what's actually circulating in the plasma of 5 animals, the parent drug, any metabolites, the time 6 course of when they reach their maximum concentration, 7 both of the parents and metabolites. Are the 8 metabolites so-called "active" in various assays. And 9 you want to find out in humans if these same chemical 10 species are circulating in the same sorts -- in 11 general, the same sorts of proportions because it might 12 be that humans produce a metabolite that doesn't exist 13 in the animals, or in the animal species that have been 14 studied. In which case the animals have really not 15 been exposed to the circulating species that may 16 actually be toxic in humans, so you have to search for 17 another animal species to do the toxicity. This is 18 very important to learn very early in the proceedings. 19 Anyway, that's an important aspect, the 20 animal studies. 21 If I could have the next slide. 22 Let's move to human studies. As I say, these 23 rules apply to drugs which have an intention ultimately 24 to have some utility against a disease or as a 25 diagnostic, but it's well-accepted, I believe, that at PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 228 1 least in phase one of the early stages of development 2 in humans, the subjects enrolled in the early studies 3 cannot and will not benefit from the treatment. That's 4 because usually they are normal volunteers and they 5 have no problem from which drug can give them a 6 benefit. And this is also true even in patients. 7 Because these studies are usually designed to look at 8 tolerability, single dose and ultimately multiple dose. 9 They reach steady state, but nonetheless they're not 10 designed to look at effectiveness. 11 So if a patient has alzheimer's disease or 12 epilepsy and the study is one dose or a week long, 13 there's no hope that that pay will benefit from the 14 treatment. 15 So, again, to go back to this point, phase 16 one in general, although one could start to look at 17 preliminary efficacy in phase one, but phase one in 18 general can really be seen as representing exposure to 19 nothing other than a pure potential toxin. Even if 20 ultimately the drug is shown to be effective and safe 21 for patients for the particular indications, certainly 22 the subjects enrolled in these early studies are being 23 exposed to a toxin to them and nothing else. So how 24 can we justify what are the safeguards that exist to 25 permit this to proceed. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 229 1 So if I could have the next slide, please. 2 And, again, I'm sure you know a lot, if not 3 all of this, certainly why do we give it to humans at 4 all? Well, because in order to get a drug approved for 5 humans, it has to be studied in humans. That's part of 6 the law and that's almost always true. There might be 7 rare exceptions, but as a general policy, you have to 8 study it and approve it to be safe and effective in 9 humans if you want to market it. So it ultimately has 10 to be studied in humans. So we need to be able to do 11 this. 12 Well, of course, these phase one studies, and 13 all studies, obviously, are required informed consent 14 with certain elements which you all know about must be 15 obtained. There has to be local IRB approval, of 16 course, as you know, and then we are obliged to review 17 these studies. All human studies have to be submitted 18 to us before they may be undertaken. 19 It's a little known fact that for the most 20 part sponsors don't have to wait to hear what we think 21 about these studies before they're permitted to perform 22 the studies. 23 It's only in the very initial submission of 24 investigation of the drug application, the sponsor has 25 to wait for 30 days while we have to review the data, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 230 1 the previous human data, if there are any animal 2 studies and the protocol and decide whether or not they 3 can proceed. Or, if they are permitted to proceed, all 4 subsequent protocols which must be submitted before 5 they are undertaken can be started the day they're 6 submitted. They don't have to wait for the agency's 7 response. 8 Could I have the next slide? 9 Well, what does our review consist of? Well, 10 many things. But there are basically four reasons. 11 There are actually a few more, but there are four main 12 reasons why we can say, no, you may not do this study 13 that you're proposing. What are they? 14 Well, one is that the investigator is 15 unqualified. We almost never make use of this 16 criterion. We have a list of investigators, for 17 example, who have been disqualified. We check that 18 list when somebody submits the name of an investigator, 19 but one almost never finds the particular or the 20 proposed investigator on that list. So we almost never 21 -- plus, if someone is a licensed physician in general, 22 we consider them qualified. 23 Well, another criteria that would result in a 24 study being placed on what we call clinical hold would 25 be that the investigator's brochure is misleading, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 231 1 erroneous, or materially incomplete. The 2 investigator's brochure is a document produced by a 3 drug company, handed out to their investigators which 4 is supposed to have all the relevant animal and 5 previous human data, if there is any, information that 6 would permit the investigator to use the drug safely 7 and intelligently. It's in a sense analogous to 8 product labeling for an investigational drug. 9 If it's misleading, if it's erroneous, if 10 it's promotional, and many of them are on first blush, 11 it can be a reason to prevent the study in and of 12 itself from proceeding. And we have certainly used 13 this as a reason to place the study on clinical hold. 14 If I could have the next slide. 15 The other two reasons are the reasons that we 16 invariably do invoke when we do place a so-called 17 "clinical hold." That is to say that subjects are 18 exposed to unreasonable and significant risk. And, of 19 course, these are called in terms of art, these are 20 obvious subject to individual judgment as to whether or 21 not these thresholds have been met, but nonetheless, 22 for example, the typical thing might be that animals 23 experiencing sudden death, let's say at all doses, and 24 we have no explanation for it, we would say, well, 25 that's -- until a sponsor understands that a little PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 232 1 better or there's some significant hematologic -- 2 [Laughter.] 3 DR. KATZ: -- well, you'd be surprised, some 4 people don't impose that. But we take these things 5 very -- 6 [Laughter.] 7 DR. KATZ: -- we take these things fairly 8 seriously. So that's the kind of thing we would say, 9 well, you can't do this until you learn more about it. 10 And sometimes these sorts of things can be explained 11 away. 12 For example, it can be shown that a 13 particular adverse event is due to a specific 14 metabolite that a specific species makes. Ultimately, 15 and maybe most other species don't have this problem, 16 don't make a particular metabolite and ultimately if 17 humans are exposed we may see that in fact humans don't 18 make that metabolite. So that's the sort of thing that 19 can get somebody out of it. But that would be a 20 reason. Or there's insufficient information to assess 21 the risk. In other words, the sponsor hasn't done the 22 traditionally required animal studies, this sort of 23 thing. 24 Okay. If I could have the next slide. 25 And as I mentioned before there is this PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 233 1 linkage, we hope, between the animal studies and the 2 human studies and so as additional human studies 3 proceed or particularly longer duration, we ask for the 4 longer-duration animal studies to proceed them. There 5 are additional -- if significant numbers of women of 6 childbearing potential are to be exposed, then we would 7 expect that the required animal studies looking at 8 reproductive function, teratogenic potential of the 9 drug are done before that particular population is 10 exposed. 11 Here, again, when I say "circulating species" 12 I'm going back to what I said before, that is to say, 13 once you learn in humans what the metabolic profile is 14 you want to make sure that the animals in which you 15 performed the toxicity studies have been exposed to 16 those particular circulating chemicals. 17 And, of course, as exposure -- as development 18 goes on, data that are occurring in humans obviously 19 has a critical influence of subsequent human studies 20 regardless of what the animal studies show. So if the 21 animals are clean but the humans are experiencing some 22 particular adverse event at a particular dose, this 23 sort of thing obviously has a profound effect on the 24 next clinical studies that are proposed. 25 The next slide. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 234 1 And, again, of course, one can approve a drug 2 for marketing in this country if all you have is animal 3 data. So really, obviously, human data are paramount. 4 It has to be shown to be a drug before it can be 5 approved, it has to be shown to be safe at the doses 6 proposed with the proposed labeling in humans. That 7 makes sense, I think. 8 However, there -- even if humans appear to be 9 tolerating a drug relatively well, I think there are 10 places where the animal studies either completely 11 substitute for an absence of human data, at the time of 12 decision about marketing is made, or other 13 circumstances, and I'll talk about that. 14 Basically, for example, carcinogenicity 15 studies. For most drugs to be administered 16 chronically, we require long-term animal 17 carcinogenicity studies. We get no information in a 18 typical drug development program about whether or not 19 the drug is potentially carcinogenic in humans. 20 Usually you need many more patients to be exposed. 21 So we rely very heavily on a provisional 22 conclusion about whether or not a drug could be 23 carcinogenic in humans based entirely on animal 24 studies. Similarly with reproductive toxicity or 25 teratogenicity. That sort of data is not obtained in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 235 1 humans prior to marketing. And sometimes even though 2 there may be other sorts of toxicities that we are 3 going to be very worried about at the time of approval 4 even if the humans seem to be free of any significant 5 toxicity sometimes you can see pathologic changes in 6 animals and in many species in animals and in doses or 7 exposure that humans will be seeing, the humans my look 8 fine, because you haven't looked appropriately. 9 We've had a number of examples where animals 10 have had lesions in the brain, the humans look fine 11 because we didn't really know how to monitor for these 12 potential lesions in humans and we've asked folks to 13 stop drug development to see if they could develop a 14 way to monitor for it in animals before other human 15 studies proceed. So even safe passage in humans 16 doesn't necessarily imply that the drug is not toxic. 17 One has to know how to look for specific toxicities and 18 a lot of that is driven from the animal studies. 19 And I think that's it. So I'll stop there. 20 CHAIRPERSON MARSHALL: Thank you very much, 21 that was a wonderful overview. 22 Let's just go right into questions. Mark. 23 MR. BARNES: I have something rather 24 provocative to say. So you'll excuse me, but I guess 25 that's our role. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 236 1 This is in regard to Richard Wiles's point 2 that he did not, in his remarks, that he did see that 3 if there were human studies that it was somehow 4 different from medical research studies because there 5 would not be an actual benefit to the participant in 6 the study. And I simply am not convinced that that's 7 true. 8 I'm an old public health person, and, you 9 know, even though the benefit may not be personal, 10 immediate, and direct, there could in fact be an 11 attenuated benefit to everyone in society including, 12 but not limited to the participant in the research if 13 in fact there is scientific validity to human studies 14 and if the human studies lead tot approval of a 15 pesticide which greatly increases crop yields and 16 therefore increases profits of farmers and crop yields 17 in developing countries and feeds more children and 18 everything else. So, I'm completely -- I have to tell 19 you, I'm completely unconvinced about -- I understand 20 that the models are not exactly the same, but there is 21 -- but, you know, there are population-wide benefits to 22 doing some things that may not be immediately apparent. 23 That leads me to the next point which is 24 that, you know, I have to tell you, I'm from a -- I've 25 said this before, but I'm from a farming family in a PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 237 1 very gothic corner of Alabama. And when I was a child 2 -- my family farmed this same farmland for a couple 3 hundred years, and when I was a child I spent the 4 summers with my great grandfather who is a farmer and 5 had sharecroppers who worked his land and he worked 6 some of his own land. And I can tell you that every 7 year, you know, when July and August come around and 8 people start wondering what the crop yields and what's 9 going to happen with the cotton and the corn crop this 10 year. 11 I can tell you in my childhood I remember 12 people, you know, black men and white men standing 13 around talking about it and they would say, "Thank God 14 for Dow Chemical Company." And, you know, the reason 15 is, is because their crop yield that year meant whether 16 -- you know, whether a bunch of poor kids were going to 17 have a new coat and new shoes and everything else or 18 not. 19 So that's all to say that, you know, that 20 there really are -- I don't know anything about the 21 scientific validity of human studies or not human 22 studies because I'm not a scientist. But I can tell 23 you that there are direct benefits, and if there is 24 some scientific validity to these human studies, and I 25 presume there must be some because the -- you know, the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 238 1 pesticide industry presumably wouldn't have offered and 2 EPA wouldn't have accepted, you know, those studies as 3 some evidence of something unless there were some 4 scientific validity to it. 5 And, you know, I'm not convinced but that 6 there is not benefit and there is a hidden -- there's a 7 hidden side to this story, and I'm sorry industry is 8 not here to present it, although I guess that falls to 9 us to say industry's piece. But, you know, there are 10 -- the hidden costs that we're trying to prevent here 11 is the cost of unwanted side effects in humans. But 12 there is another hidden cost which is, if needed 13 pesticides are not approved, then we don't even know 14 what that cost is. 15 MR. WILES: Well, there's no shortage of 16 pesticides out there. And I agree with you, pesticides 17 are an important component of food production. This is 18 not about taking pesticides off the market. And there 19 is definitely no shortage of food, witness our $70 20 billion farm bill that just went to bail out farmers 21 who are overproducing to such an extent that prices are 22 at all-time lows. So the starving children analysis -- 23 the starving child that will be saved by a human study, 24 I just don't think that that really is supported by the 25 actual data. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 239 1 I'm not saying that we don't need pesticides 2 and we're definitely not against pesticides. We are 3 very much for pesticides when they're used safely and 4 regulated properly. There's also, like I said, no 5 shortage of pesticides out there. In fact, there's 6 never been a case, in spite of industry's hysteria to 7 the contrary, where the imminent collapse of the food 8 supply or even really any significant price increase at 9 the consumer level occurred when a pesticide was 10 canceled, setting aside human data. 11 Farmers have been impacted, that's true. But 12 not nearly as much as the Farm Bureau and others will 13 tell you. And I think it's very obvious that the 14 biggest impact and threat to farmers is not whether or 15 not they have pesticide X and human studies are not 16 going to really have anything to do with whether or not 17 they do have pesticide X. So maybe there is some 18 benefit, I suppose, in a hypothetical scenario, but I 19 don't think that really has any real world impact. 20 As far as the benefits go, I guess what I'm 21 trying to say is that it's clear that a drug in theory 22 -- you're developing the drug with -- there's an 23 intended benefit to some people who are sick. And sine 24 people will be taking the drug, you want to test it on 25 people. This is much different -- what you are trying PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 240 1 to do is grow food and kill insects and control weeds 2 and control fungi, and then in the end protect the 3 population from a small residual amount of a compound. 4 There has really never been a case when if the 5 industry had actually not opposed the safety standards 6 that are required by law, and all the safety standards 7 that are required by law have been applied, there 8 aren't very many cases when that happened, when full 9 safety standards were in effect where there were 10 significant human harm done. Where you get into 11 problems is when industry is push to not apply the 12 safety standards that are required to be applied to the 13 animal data and you get chemicals on the market that 14 either have an incomplete database or where safety 15 margins have been eroded due to pressure from industry 16 like these human studies. 17 So, it is a very fundamentally different set 18 up here sort of trying to control pesticide exposures 19 to the lowest amount that you can possibly get while 20 you still have efficacy in pest control versus 21 determining a dose for a drug that's going to be 22 directly taken by people. 23 So we are sympathetic that farmers -- in 24 fact, the environmental working group is probably the 25 central group that works on farm policy in the United PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 241 1 States and we have spent a lot of time trying to get 2 more money to more farmers in the past year. So we are 3 well versed in this. And I don't think that the human 4 study issue is really related to farmer profitability 5 or pesticide availability. 6 CHAIRPERSON MARSHALL: Bob and then Elliot. 7 DR. R. LEVINE: Thank you. Mr. Wiles was 8 pretty thorough in his critique of the direct dosing 9 studies and I think he was quite accurate. However, 10 one could equally critique the biomonitoring studies. 11 If you're going to just take the samples of blood, for 12 example, from the N. Hanes [ph] study and try to find 13 the correlation between one chemical out of the 500 to 14 1,000 that our population has been exposed to and try 15 to establish a significant correlation between the 16 presence of that chemical and any particular mutagenic 17 or teratogenic result, you're going to have to look at 18 even more subjects than they have in the N. Hanes 19 studies which is many, many millions. 20 I also want to comment briefly something 21 Rusty Katz said to extend it. You pointed out that an 22 analogy is in phase one drug testing. Much of the 23 criticism of testing pesticides in people is that 24 you're exposing people to risks where there's no 25 expectation of direct benefit to that person. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 242 1 In phase one oncology studies, not only are 2 you exposing people to risks, but I don't think most 3 people here know how they're done. It's a dose 4 escalation design and you keep pushing the dose up 5 until two out of three patients get life-threatening 6 toxicity. That we call the dose above the maximum 7 tolerated dose. Then we drop back one dose level. So 8 we are talking about very, very heavy risks where 9 there's similarly no -- virtually no possibility of 10 direct benefit. 11 In the study done at the National Cancer 12 Institute in 1,200-and-some-odd consecutive phase one 13 drug trial subjects in oncology they did find that 0.16 14 percent of them got a complete remission. So I can't 15 say no possibility. 16 MR. WILES: I'll go and then you can respond. 17 On the N. Hanes sample size business, we agree with 18 you. I mean, I definitely agree, you're not going to 19 be able to do any real epidemiology or find any cause 20 and effect relationship between those things. But 21 here's how bad the situation is why we need that. 22 Because the situation is so bad that we don't know 23 where the pesticides are or if they show up in people. 24 For example, EPA has no idea, really where these 25 pesticides end up after they go through all of these PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 243 1 approvals. And when they do find out, it often drives 2 regulatory decision-making. What really got the 3 insecticide durigban chlorpurifos, the most widely used 4 indoor insecticide off the market were two things; one, 5 a developmental neurotoxicity study in rats that showed 6 delayed and persistent effects in rat morphology in the 7 brain that have never been seen before and we don't 8 want to do that on humans, I hope. And also some 9 biomonitoring that showed that the metabolites of 10 durigban were in about 90 of school children and about 11 85 percent of the N. Hanes participants. 12 EPA had no idea that the exposure was that 13 prevalent. They didn't make any dose calculations 14 based on that, but that was very important to know 15 that. And if you don't have the -- a lot of these 16 pesticides are very complicate chemistry. Some of them 17 are, we would even say a good chemistry because they're 18 specific, they're looking for a toxic mechanism in an 19 insect that may not exist in humans and all those kinds 20 of things. But it makes them very difficult to find. 21 They're not picked up by your standard sort of OP, 22 nitrogen scans and those kind of things. You really 23 need to know -- and you need to have industry basically 24 show you how to do it. And they're not required to, 25 they don't volunteer it. So when you get into these PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 244 1 situations, the simple fact of knowing just what the 2 percentage of the population has this in the urine or 3 blood, very important information. 4 CHAIRPERSON MARSHALL: Elliot. 5 DR. DORFF: Two questions, one very specific 6 and one much moe general. The specific thing is, part 7 of the way in which the agricultural business has tried 8 to deal with problems with pesticides is to have 9 genetically engineered foods. And I was sort of 10 wondering whether, you know, either the Food and Drug 11 Administration or EPA or anything like that has begun 12 -- has done testing on toxicity and the bioengineer of 13 foods, and in terms of their effects on human beings? 14 The other question that I have is much more 15 general which is that if you -- what do you want us to 16 do? Right? In other words, if you had your druthers, 17 what would you suggest to us to suggest to OHRP and all 18 and the rest? 19 MR. WILES: Is this for me? I'll go. 20 Okay. We would like this committee to 21 recommend a clear prohibition on the testing of 22 pesticides, pollutants, and chemicals regulated under 23 the Toxic Substance Control Act. We want the direct 24 dosing studies banned. We would like -- you know, it's 25 got to be that type. And it would be great if we PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 245 1 weren't in the real world and we could talk about 2 science, it would be good to do. We are so -- for good 3 science, I can't even tell you. We make our entire 4 living off of good science and finding out when there 5 hasn't been good science. 6 That's basically how we exist. We find out 7 where industry has done bad science and industry and 8 EPA has capitulated to bad science and that's when we 9 win. We never -- we can't make any progress in our 10 business on hysteria in spite of what people like to 11 think. So, you know, we're all for good science. 12 On GMOs, we don't have a position on GMOs 13 except that we have an observation. We don't work on 14 it, we're not funded to work on it. The observation is 15 this, is that when the chemical industry Monsanto, in 16 particular, came to the market with genetically 17 modified foods, the first thing they did was to try to 18 avoid comprehensive testing by getting a determination 19 out of the FDA that genetically modified food was 20 substantially similar to regular food. And they got 21 that. And that has been a big boon to the industry 22 because they have not had to test the food through a 23 standard battery of toxicity tests. 24 Now, I understand the difficulties with that 25 in that, you know, what's the maximum tolerated dose of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 246 1 a potato. You know, you get to some obvious 2 methodological issues designing the study. In our view 3 though, that's not a good enough reason to give the 4 industry a complete pass on the testing requirement. 5 What the requirement should have been is, all right, 6 you guys, let's come off with some real studies here so 7 that we can look for the obvious effects. There have 8 been some booboos and no major disasters yet, but 9 that's mostly because we're not looking very hard at 10 the more subtle long-term impacts probably. Like with 11 most of these things, 98 percent of what's done will be 12 fine. Then there will be these things that slip 13 through the cracks because we don't have a 14 comprehensive system in place to look for it. 15 So we're against not testing GMOs, we don't 16 have any particular position at this point on GMOs, per 17 se. 18 DR. SANDLER: I would just like to make one 19 point. And that is that I don't think there's a mutual 20 exclusivity between say animal studies and human 21 studies. For example, there is nothing that human 22 studies would prevent the testing -- the reproductive 23 testing of chlopurofos or any other active ingredient 24 to determine the reproductive effects. And certainly I 25 would think that if there are specific endpoints PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 247 1 meaning, you know, health consequences that you would 2 look at doing both as to be realistic and utilize the 3 specific benefits from each type of testing in the 4 appropriate fashion as I'm sure most government 5 agencies certainly try and frequently do. 6 MR. WILES: Are you suggesting that we should 7 do direct dose dusting for developmental effects in 8 humans? 9 DR. SANDLER: Of course not. I mean, that's 10 -- 11 MR. WILES: I just was confused. 12 DR. SANDLER: -- I didn't say that and you 13 know I didn't say that. 14 MR. WILES: That's why I don't want to walk 15 away here -- 16 DR. SANDLER: That's not nice to do here. 17 MR. WILES: -- with the impression you did. 18 Well then what did you say? 19 DR. SANDLER: I said that human testing 20 wouldn't prevent doing animal testing for developmental 21 defects. 22 MR. BARNES: Can you answer the question that 23 was asked though which is, what do you guys want us to 24 do as a committee? What do you two guys want us to do? 25 DR. SANDLER: My opinion is having come here PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 248 1 and asked to do what I'm supposed to do and that is 2 consider the effective use of all aspects of science to 3 determine the questions that need to be asked. 4 If, for example, human studies can help you 5 with metabolites to see if there's a difference between 6 animals and humans and you don't need to dose somebody 7 at a huge level to do that, you certainly can dose them 8 at very low levels. You can determine just in certain 9 populations how colon estrace levels jump at what 10 levels. Do they go up and down real quickly at certain 11 doses? When does the switch from say 10 percent to 25 12 percent, is that strictly dose response? Or does it do 13 -- does it respond to a different curve, if you will? 14 So there are some real fine points that can be 15 extremely useful without saying that we're going to 16 take humans and dose them to see if they have children 17 who have birth defects. Clearly no one wants to do 18 that. 19 CHAIRPERSON MARSHALL: Judy. And anyone who 20 wants to come from the ex-officio or public members, 21 please step up to the microphone. 22 DR. SIEGEL: While I do agree that there is 23 benefit in human testing the way you're talking about 24 it, I think my concern is when you look at what we'll 25 call singleace tendon dose tolerance stuff for no PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 249 1 effect levels or for maximum tolerated dose levels in 2 drug development, you're looking at the beginning of a 3 process. I think what I was reacting to, again, what 4 we were reading was these studies seemed to be used as 5 an end product that would help make regulations. And I 6 think that's in fact what I was reacting to when I did 7 this. Because, as you see, this use of that type of 8 data is really the beginning of a very long process. 9 It's not the end. 10 DR. SANDLER: Let me just comment that I 11 think what you said was extraordinarily important and 12 my question is, let's find out exactly how those 13 studies were done, how they were presented, and the way 14 that they were performed because I think that would 15 answer it. 16 I mean, we've heard one issue on that and 17 certainly a lot of rhetoric, or whatever you want to 18 call the term, on this issue. I think it bears, you 19 know, some of the day of light to make sure that in 20 fact those studies were performed in that way and that 21 certain things were done in certain ways. If they 22 were, they were. If they -- and that needs to be 23 changed. If they weren't, then that needs to come out 24 too. 25 CHAIRPERSON MARSHALL: Mr. Katz. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 250 1 DR. KATZ: Yes, again, I've been asked, I 2 guess, from both sides of the -- what we want. I 3 cannot speak for the agency -- 4 [Laughter.] 5 DR. KATZ: -- about what we want. And I'm 6 happy to be able to say that. This is -- I'm not with 7 that part of the agency that deals with these issues, 8 so I abstain. 9 [Laughter.] 10 CHAIRPERSON MARSHALL: Margaret. And if 11 you're not speaking, please turn your microphone off. 12 There are a couple of mikes on. Yes, thank you. 13 MS. BORWHAT: Can any of you answer how 14 effective extrapolating from animals to humans is in 15 the various fields? You're taking a certain level as a 16 starting point and in other ways you're looking at 17 different end points. How has this level stood up over 18 time? 19 DR. KATZ: Well, that's something I can try 20 again from my point of view answer. We certainly would 21 not rely in any meaningful way particularly with regard 22 to effectiveness, for a particular indication from the 23 point of view of a drug development on what happens in 24 animals with the possible exception of there are 25 proposed regulations that deal with how to develop PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 251 1 drugs to treat antidotes. But you can't actually do 2 the studies in humans, ethically. So there is some 3 question about that. Those are pending proposed 4 regulations. But in a typical drug development case 5 where there's a naturally occurring disease, half the 6 time there aren't even animal models that even speak to 7 the question of whether or not there will be -- the 8 drug is going to be effective. So from an 9 effectiveness point of view it's essentially, and from 10 my point of view, not relevant. Safety is a different 11 issue. Sometimes the animals predict very well and 12 sometimes they don't predict at all. 13 CHAIRPERSON MARSHALL: Bob, you comment is on 14 point? 15 DR. R. LEVINE: Yes. 16 CHAIRPERSON MARSHALL: Yes, please go ahead. 17 DR. R. LEVINE: A footnote to that is that 18 one of the antidotes that would come under these 19 proposed regs would be the anti-colon estrace 20 inhibitors so that there would be things that would be 21 designed to prevent the toxicities that we've been 22 talking about this afternoon. 23 CHAIRPERSON MARSHALL: Thank you. 24 MR. WILES: Can I take a shot at this 25 question on the animal -- PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 252 1 CHAIRPERSON MARSHALL: Sure. 2 MR. WILES: Remember what you're trying to do 3 here is you take a no-effect level and the law and regs 4 which require you to take a no effect level in the most 5 sensitive species and then go down at least 100 and 6 under our reading of FQPA, a thousandfold. And in how 7 many cases has that failed us? Also FQPA requires some 8 more things. You have to look at all routes of 9 exposure when you determine the thing. You have to 10 look at any chemical with a common mechanism of 11 toxicity and add it all up from all routes. Okay. So 12 you get to a very safe system, if you will, with lots 13 of conservatism which is what industry will argue ad 14 nauseam that this is overly conservative. 15 And it's our view that if you take -- because 16 this regulation is so fundamentally different, you're 17 trying to get the doses down to the lowest you can. 18 You start with a no-effect level, go down a thousand 19 times from there and then add up all routes of exposure 20 to see if you no-go even lower. We'd say you would be 21 very hard pressed to find cases where -- when that 22 system was used, not when we ended up not doing that. 23 But when that was used where you had adverse impacts 24 and then I think you'd even be further hard pressed to 25 find a point where you used all that system that's in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 253 1 the law the way it's supposed to be used and didn't 2 have an adverse impact but then would have found the 3 adverse impact if you've done direct dosing of humans. 4 I don't think that scenario really holds up. 5 And that's why I get back to reality. I hear what 6 you're saying, but in reality this is what you're 7 talking about. If you open the door just a little bit, 8 you'll get some situation down the road where some 9 variation on a study you thought was fine all of a 10 sudden turns into something else and then we're into a 11 totally different ball game. 12 CHAIRPERSON MARSHALL: Thank you. And could 13 you just tell us who you are? 14 MR. McALLISTER: Yes. My name is Ray 15 McAllister. I'm the Vice President for Science and 16 Regulatory Affairs for CropLife America. 17 And my favorite quote from Richard Wiles is, 18 "I am not a scientist." The information that's been 19 presented to the panel in advance, the two documents, 20 it's obviously very biased in one single direction, one 21 extreme direction. It's been produced by an activist 22 group with a very definite political agenda. 23 We in industry learned of this discussion 24 with only a few days notice. We have been unable to 25 provide counterbalancing background information or to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 254 1 prepare well to inform you today of our positions. I 2 can make a few comments, but I can't provide 3 comprehensive detail. 4 Mr. Wiles has said we don't support 5 biomonitoring that we indeed discourage it. And that 6 is basically false. We have encouraged and supported 7 biomonitoring. The CDC is currently conducting 8 biomonitoring. Their first report came out a little 9 over a year ago showing the presence of certain 10 metabolites of pesticides and the CDC is expanding that 11 each year the number of compounds, including pesticides 12 that are to be included in these studies in 13 biomonitoring. 14 We have cooperated with and supported a long 15 going, long-term agricultural health study which looks 16 at the health effects of pesticides and the presence of 17 pesticide exposure to farm families. Our industry has 18 financially supported a separate companion farm family 19 exposure study looking at specific exposures of a few 20 pesticides to farm families, both to spouses and 21 children of farm operators so that they can be tied to 22 specific application events. 23 The human studies we've been talking about 24 are not conducted in a scientific and ethical vacuum. 25 They each are reviewed by institutional review boards, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 255 1 not the independent review boards mentioned in these 2 papers. They are conducted by the same laboratories, 3 the same scientists who do the phase one drug trials, 4 they're the same folks. 5 EPA, at least prior to 1998 when they changed 6 their policy has reviewed the science of the studies 7 and passed judgment. When they have reservations about 8 the science in the study they will express it. But 9 they have looked at the science there and passed 10 judgment. 11 If EPA won't consider the study in its 12 regulatory program, there is no incentive for industry 13 to conduct the study. They're expensive and we're not 14 going to be out conducting studies simply for the 15 purpose of having that information if there's no 16 regulatory use for it. 17 In general pesticide testing in animal models 18 is much more thorough prior to any conducting of human 19 testing. And as has been mentioned here today, human 20 may produce metabolites not present in animals. It 21 seems to me that the only way you can conduct 22 biomonitoring efficiently and effectively is if you 23 know what metabolites are produced in the human system. 24 Yes, the volunteers in these studies are 25 paid. So are the volunteers in all of the drug tests. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 2 56 1 My son, my 21-year-old son was a volunteer in a pain 2 medication study for dental work and he was paid, yet 3 he was still a volunteer. 4 EPA can reasonably apply the Common Rule to 5 studies involving pesticides and other chemicals. It 6 seems to me that's a fairly straightforward regulatory 7 approach to handling these studies. 8 Thank you. 9 CHAIRPERSON MARSHALL: Thank you very much. 10 I think Kate Gottfried wants to speak perhaps to one of 11 your initial observations. 12 MS. GOTTFRIED: Just a point of clarification 13 with respect to your awareness of the agenda item. On 14 or about April 15th, CropLife America was contacted and 15 Doug Nelson, the Senior Vice President and General 16 Counsel actually had originally committed to speaking 17 on the panel. So the information in fact was out there 18 several weeks ago. 19 MR. McALLISTER: April 15th is not several 20 weeks ago. 21 MS. GOTTFRIED: Well, it's two weeks ago. 22 MR. McALLISTER: Now, we -- I don't know what 23 the purpose of the panel is in discussing this subject 24 and that's been asked by a couple of folks on the panel 25 today. If the panel is to have a future role in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 257 1 providing input either to EPA or through other means on 2 how this issue is resolved, we are certainly willing to 3 provide you background information. 4 CHAIRPERSON MARSHALL: Thank you very much. 5 Abbey. 6 MR. WILES: Can I clarify on that? 7 CHAIRPERSON MARSHALL: Abbey. 8 MS. MEYERS: The statement that most 9 volunteers in drug studies are paid, what makes you 10 think that? 11 Do you want to answer that? 12 DR. SHAMOO: Nobody really knows, but there 13 are a lot of volunteers who don't get paid a cent. So 14 I don't know what the breakdown is, but I know 15 hundreds, thousands who don't get paid. But at the 16 same time there is overpayment, you know, in some 17 cases. 18 MS. MEYERS: I think what is probably 19 happening is that in academia normally they're not 20 paid. If they have a disease and they're in research 21 for their disease, but maybe because of all the 22 commercial interest in this kind of testing, maybe 23 families are paid when they take their children in fro 24 pediatric. Judith, do you know? Do you have an 25 answer? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 258 1 DR. KATZ: Certainly subjects in drug studies 2 are paid. Not all perhaps. I have no idea what the 3 numbers are, what the rate is, but certainly as a 4 principal of whether or not somebody can be considered 5 a volunteer and also be paid there are many such 6 subjects. 7 CHAIRPERSON MARSHALL: I want to continue 8 this discussion and we are sort of close to time. But 9 I'm going to just give us a couple of minutes before we 10 break and then I'm going to have a conversation with 11 the committee about where we go from here. 12 But I do want to point out that the ground 13 rules that I generally lay out at the beginning of the 14 meeting call for civility in terms of discourse and 15 that is something that I will impose. So, the 16 expectation is that when you make remarks or present 17 before the committee that what you present are facts 18 and not conjecture. So that's a ground rule for 19 everyone. And that we certainly, I think, on this 20 committee take great pains to be fair in terms of our 21 procedure and in terms of inviting everyone who should 22 be at the table to the table and make sure that they 23 have an opportunity for discussion and probably go 24 beyond most FACA committees in terms of providing time 25 on the agenda for anyone who hasn't been invited to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 259 1 have an opportunity to do so. 2 So I'm sorry if you feel as though we haven't 3 been fair in terms of our approach, but I guess my 4 sense is that we have. 5 Judy. 6 DR. SIEGEL: I think as far as payment is 7 concerned, if you're talking about healthy volunteer 8 studies, I think probably the higher likelihood that 9 you will see payment, these are people for whom there 10 probably is no possibility for a direct benefit and I 11 know that these people are paid for their time and 12 sometimes for their inconvenience. I think the amount 13 their paid has been the subject of a lot of discourse 14 around, but the fact is that these are people who are 15 paid for their participation. 16 I think when you go into the later phases 17 where you're actually treating patient populations the 18 payments more have to do with remuneration for travel, 19 time spent, meals, but it's of a different type than 20 paying for someone who has no direct benefit. 21 MS. MEYERS: [Off mic.] 22 [Laughter.] 23 CHAIRPERSON MARSHALL: One last remark and 24 then unless other committee members or anyone else who 25 is in the room today would like to ask a question, I'm PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 260 1 going to thank our panelists and move on to a committee 2 discussion. Mark has his hand -- 3 MR. BARNES: I guess my question or thought 4 is, where do we go from here with this particular 5 issue? And it seems to me that -- I mean, as I sort of 6 thought about what this issue really is and what -- 7 it's actually a subspecies of a larger issue which is 8 sort of, what is research? What kind of research ought 9 to be -- what ought to be regarded as research that is 10 subject to the Common Rule. That's really sort of an 11 abstract level. I think that's the issue. And it's 12 not an easy issue because if you -- because of the 13 particular human risk in this area, we decide that 14 there ought to be a recommendation at some point from 15 this committee with a discussion and a deliberative 16 process that these kinds of things ought to be covered 17 by the Common Rule. 18 Then the question becomes, well, this is 19 private industry performing studies alone and not with 20 federal funding and not under federal assurance, then 21 what about all the social science research that private 22 industry does that also, you know, if you extend it 23 here, why not extend it there as well. And so there 24 really are some very difficult issues about line 25 drawing on this. Which reminds me of a point that Bob PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 261 1 Levine made earlier today which is on the sort of 2 generic issue of, you know, that we're all grappling 3 with, sort of the frontier of the Common Rule which is, 4 when does quality assurance become research? When does 5 quality improvement become research? When do clinical 6 anecdotal studies or surveys of existing patients who 7 were treated in the clinically appropriate way, when 8 does that become research and need to go before the 9 IRB? 10 So, I don't know. Where this sort of takes 11 me back is that there may be something that needs to go 12 on our agenda as a committee which is not so much, you 13 know, about EPA specifically and this recommendation 14 and that recommendation from the three gentlemen who 15 have spoken today and the gentleman from the EPA who 16 spoke. But, instead, really, more toward the generic 17 issue of, you know, what are the five top issues that 18 need to be looked at in regard to what is research 19 under the Common Rule and how should we recommend new 20 interpretations of the Common Rule to cover that which 21 ought to be covered? 22 CHAIRPERSON MARSHALL: Thank you, Mark. 23 Here's what I would like to do as we proceed 24 is I would like to thank all of the panel members very 25 much for your preparation and your remarks and your PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 262 1 willingness to be here today. We very much appreciate 2 it. 3 [Applause.] 4 CHAIRPERSON MARSHALL: I would like to give 5 us somewhere between five and ten minutes as a 6 committee to discuss where we go and have a general 7 discussion. Then we will have a break and move on to 8 informed consent. 9 So, thank you. 10 [Pause.] 11 DR. FLEISCHMAN: I think there are some in 12 the room who think we're breaking, Madam Chairperson. 13 CHAIRPERSON MARSHALL: We are not breaking. 14 I mean, you are certainly entitled to get up if you so 15 choose, but we're not going to break for another ten 16 minutes. 17 Alan. 18 DR. FLEISCHMAN: Yes. I think, Mark, I have 19 some concerns with how you've conceptualized the 20 problem. I mean, I do think that it would be greatly 21 beneficial for us to talk about the issues you've just 22 put on the table. But we've heard about and there have 23 been other conferences that have addressed the question 24 of putting toxic substances into humans in order to 25 find out how toxic they are. And I was quite taken by PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 263 1 Dr. Katz's presentation, but I don't think it's 2 relevant really to what we're talking about since those 3 toxic substances are intended to be beneficial. These 4 toxic substances are intended to kill biologic entities 5 other than humans and we want to try not to kill the 6 humans while we hurt the mosquitos or whatever else. 7 It seems to me that -- and I do think we need 8 the insight of the industry representative. But the 9 gentleman at the microphone argued that he didn't seem 10 to have any problem with the Common Rule being part of 11 the research in human subjects around pesticides. Now, 12 he may have said that inadvertently, I don't know, but 13 he kind of said that, I think. 14 And one of the things I would really like to 15 understand better, and I'm sorry that Mr. Jordan had to 16 leave, is why the Environmental Protection Agency 17 wouldn't demand such compliance in such studies even if 18 they are at the end of the line having received them 19 and don't have any way of assuring that happens 20 prospectively. They have a way of assuring it happens 21 retrospectively if they demand that they will not look 22 at such studies unless they have Common Rule 23 compliance. 24 So I just want to understand and we may not 25 be able to answer that question today. But it would PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 264 1 seem to me to be important for us to understand why 2 that isn't the case. If there is a good reason for 3 that, I would be willing to hear it. 4 And that kind of statement from NHRPAC, that 5 the Common Rule ought to apply in this kind of case is 6 an opening then to a more comprehensive look at the 7 questions Mark is raising and that Adil raised at the 8 very beginning in which he argued that this is, you 9 know, this is a problem of looking at all human 10 subjects research. I agree. But here we have a very 11 specific kind of point where we ought to be able to 12 make some headway. 13 CHAIRPERSON MARSHALL: Thank you. 14 There were other hands. Felice. Adil. 15 DR. F. LEVINE: I must be sitting next to 16 Alan at too many meetings, because some of what he said 17 I was going to. So let me just say that when Mark 18 spoke I thought -- I think there is a recurrent theme. 19 I mean, clearly we are talking about a form of human 20 subjects research. But from a number of our speakers 21 over time, Susan rose some number of meetings ago that 22 we are -- it isn't just the surveys or the work that's 23 non-federally funded or that is in industry, and 24 clearly that's a segment of work that we need to 25 consider, but there's also this, what is research that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 265 1 is in a very ancient area. Now, this clearly struck me 2 as research in that sense. 3 Alan is right, but this workplace 4 performance, product development, training, I've heard 5 from many of our ex-officio members over time, Susan 6 among them, some of our NASA folks, our AID folks that 7 sometimes both internal to the agencies as well as what 8 the agencies either support or look at there is contact 9 with humans and it is for a purpose that we as 10 researchers may say looks and feels like research, but 11 doesn't necessarily take the formal coloration of 12 research and yet involves human participants. And I 13 think somehow we need to try to engage with that in 14 terms of its fit to the Federal Rules. 15 CHAIRPERSON MARSHALL: Thank you, Felice. 16 Adil. 17 DR. SHAMOO: Well, I think I want to comment 18 on his formulation that let's deal with this issue and 19 even Alan's formulation of the problem is really 20 piecemeal. We are sort of avoiding biting the most 21 important bullet and that has been dealt with, with 22 animals. Cats and dogs, you cannot do research in this 23 country regardless if you do it in your back yard, in 24 your garage, I keep saying that without following the 25 Animal Welfare Act. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 266 1 The National Advisory Bioethics -- National 2 Bioethics Advisory Commission, NBAC, recommended that. 3 We have recommended it before NBAC. We have written 4 about it. I have said it here, I think a dozen times. 5 We need to see regardless of what the definition of 6 research is, let's agree it's research. 7 I don't care how you define it, what big 8 circle it is, define it as narrow as you want. But 9 whatever research narrowly defined should all follow 10 the Common Rule. That is to me logical, and 11 reasonable, and common sense. And I don't know why we 12 are trying to put piecemeal here for this and piecemeal 13 this for this. 14 CHAIRPERSON MARSHALL: Thank you, Adil. And 15 I have a response to that, but I will wait until the 16 end of the discussion. 17 Bob. 18 DR. R. LEVINE: The Common Rule lists six 19 categories of things that are unambiguously researched 20 and exempts them from coverage by all federal 21 regulations including research which is paid for by the 22 federal government under grants or contract. There is 23 reasons for this. I think the definition of the 24 exemptions is a bit crude. I would have defined the 25 boundaries a bit differently. But the principle, I PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 267 1 think, is important. And I want to agree with Mark's 2 agreement with me. 3 [Laughter.] 4 DR. R. LEVINE: That maybe it's time to stop 5 focusing so precisely on the definition of research and 6 to think more about what is it that we want to 7 regulate. If we keep redefining research, we will end 8 up with some very funny looking thing that looks like a 9 gerrymander and nobody will really quite understand 10 what the purpose of all of this is. 11 CHAIRPERSON MARSHALL: All right. Here is 12 where I would like to go. And, Adil, I do want to 13 respond to you. You know, you've raised the meta 14 issue, you know, about universal protections. And 15 certainly -- I mean, that goes back a long way. The 16 NBAC has recently sort of reiterated the position that 17 has been taken by ACRE and other advisory committees in 18 the past about this. And it's obviously something that 19 needs to be on our plate. 20 I guess my thought in terms of strategy is 21 that the Institute of Medicine Report on assessing the 22 overall system for protecting human subjects of 23 research will be out in September and I think that 24 there will probably be many things in there that we 25 will want to take up as a committee and it will PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 268 1 probably be a challenge just to assign priority to 2 them. 3 So my thought and plan was to invite Dr. 4 Fedderman who chairs that committee to our October 5 meeting. The report is due out in September. And I 6 think all of us, each of us and the public at large 7 will have a chance to have read the report by then, and 8 there will be, I think, a host of issues that we can 9 look at and react to and I think sort of probably 10 appropriately my sense would be that those who asked 11 the IOM to undertake that large charge will then 12 perhaps subsequently have things that will arise out of 13 their report that they would like for us to take a look 14 at too. 15 So I couldn't agree with you more in terms of 16 where we should go in the future and things that we 17 should look at. 18 To get back to this specific issue, I'm not 19 sure necessarily that the committee needs to act on it 20 in a formal way. We could, I have, you know, sort of 21 brought this before you in terms of information 22 sharing. I think that the fact that the National 23 Academies will be taking a look at it in a very 24 concrete way is something that we should take into 25 consideration. We should also take into consideration PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 269 1 that there is a voluntary moratorium on the use of data 2 from human studies at the moment by the EPA that that 3 is something that we can endorse that should continue 4 to be the state of things until the National Academies 5 is finished with their process. 6 So I'll open the floor for a few minutes for 7 discussion in terms of how the committee would like to 8 proceed or not proceed. 9 DR. CHODOSH: Let me just provide a little 10 bit of historical evidence in that. This didn't start 11 with NBAC, it started before that. And I specifically 12 challenged OPRR when they were developing the 13 regulations back in the 1970s that this was foolish to 14 just be doing this for government supported or FDA-like 15 research; and that it would seemed to me that a federal 16 organization such as NIH, OPRR, DHHS, not called that 17 at that time, should not in fact be concerned about all 18 Americans. And that was not accepted at the time as, 19 quotes, "being unrealistic." 20 CHAIRPERSON MARSHALL: Thank you. Bob. 21 DR. R. LEVINE: This is something that has 22 been considered back before the National Commission, 23 the President's Biomedical Research Council considered 24 it. The issue of extending federal regulations to 25 cover all research involving human subjects seems to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 270 1 come up every time that there is a high level advisory 2 committee. The thing that shoots it down every time is 3 that people make reference to the constitutional 4 authority of the federal government to look at to 5 review research. 6 And what has been repeated over and over 7 again, and I'll just anticipate it's going to be 8 repeated again this time is that the government has two 9 constitutional bases for regulating research. One is 10 through the conditional spending power clause, and that 11 is, if the government pays for it, it can regulate it. 12 And the other is through the interstate commerce 13 clause which creates the authority for the Food and 14 Drug Administration to regulate drugs, but only those 15 drugs that are going to be labeled for use in 16 interstate commerce. That's why we have had some 17 things like that clinic in Tennessee that made designer 18 drugs for people with cancer and the FDA couldn't get 19 at them because it all happened in Tennessee. 20 So this is what we are probably going to be 21 up against. And before we make an investment, we might 22 want to get a legal consultation first. Thank you. 23 CHAIRPERSON MARSHALL: Kate. 24 MS. GOTTFRIED: Just for those of you who 25 aren't aware, there was a hearing on the 23rd of April PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 271 1 by Senator Kennedy's committee. He and Senator Frist 2 were there and the two issues focused on, one was 3 whether or not all research ought to be regulated 4 regardless of the origin of funding, and they clearly 5 seemed that they were heading in the direction of all 6 research. We're aware that there is pending 7 legislation -- proposed legislation from both Senator 8 Kennedy as well as from Congresswoman DeGette and 9 Greenwood. They are both expected to say the same 10 thing with respect to that particular issue. One other 11 issue they just focused on during the hearing was the 12 accreditation issue. And it was clear again that they 13 embraced the notion of accreditation. The question in 14 their mind seemed to be, should it be voluntary or 15 ought it be mandatory. 16 But I do think that should legislation emerge 17 and should it ultimately be approved we will see a 18 significant shift with respect to the issue of 19 regulation of all research. 20 DR. R. LEVINE: Until there's a test of the 21 constitutionality, Mr. Frist wasn't around in the '70s, 22 but Mr. Kennedy advocated regulating all research in 23 that decade too. 24 CHAIRPERSON MARSHALL: So let me just call 25 the question that is before us in terms of the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 272 1 committee's pleasure as to pesticide testing in humans 2 or the use by the EPA of data from human studies. Bob. 3 DR. RICH: It seems to me that if the 4 committee thinks that this is an area that it wants to 5 go into, we're just getting started with the issue and 6 that we ought not to come to any kind of conclusion of 7 fact today. We obviously have not heard a balanced 8 scientific appraisal yet, and we surely would need 9 that. 10 I mean, I think the issues that Mr. Wiles 11 raised, which is to criticize the fundamental 12 scientific validity of it as a basis for saying that 13 it's fundamentally not ethical is an important 14 question. But we obviously need to hear a balanced 15 presentation on that issue, and it's clear, I think, 16 from the comments that we've heard that that was not a 17 universally accepted notion. And so I would urge us, 18 whatever we do on this, to go slow until we've actually 19 got more facts. I do sympathize with the fact that 20 whether April 15th was a sufficient notice or not, it's 21 a short time and we ought not to be rushed into this 22 process. 23 CHAIRPERSON MARSHALL: I couldn't agree more. 24 So I think really the basic -- I guess my sense is, 25 perhaps to guide the committee and its thinking is PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 273 1 knowing that National Academies are about to take this 2 up, that there is a voluntary moratorium and if I heard 3 the FDA correctly that will persist until the National 4 Academy's report process is complete. Is this 5 something that we want to put on the table or do we 6 want to wait until the process is finished at the 7 National Academies; that's the question. 8 Sandy. 9 DR. CHODOSH: My only concern is that we're 10 talking at least 18 months down the road. 11 CHAIRPERSON MARSHALL: From the Academies? 12 DR. CHODOSH: From the Academies. 13 CHAIRPERSON MARSHALL: That's true. It takes 14 a while. 15 DR. CHODOSH: And that I think that there are 16 some real basic kinds of things that we could recommend 17 at least to EPA and to Greg who chairs the Human 18 Studies Committee for the Common Rule, et cetera, on 19 how to proceed with this and that perhaps EPA needs to 20 start doing something -- and I'll bet that there are 21 other situations not dissimilar from this -- to at 22 least get some coverage of the human subjects wherever 23 they are or however they -- even the epidemiologic 24 studies, we don't know how they're handled. 25 CHAIRPERSON MARSHALL: Are you making a PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 274 1 motion that we ask HSRS to take a look at this, or that 2 we take a look at it? 3 DR. CHODOSH: I think we should get a little 4 bit more information than, you know, right now we 5 really just have a fairly biased report that's 1998. 6 CHAIRPERSON MARSHALL: Any other thoughts by 7 other committee members? 8 Alan. 9 DR. FLEISCHMAN: Could we ask Mr. Cortezzi to 10 keep us informed at each of our meetings and the 11 progress of these discussions and perhaps even bring 12 together some of the information concerning EPA and the 13 Common Rule and ask industry to give us a report in 14 writing that we could distribute so we could keep 15 current while this process goes on. 16 CHAIRPERSON MARSHALL: Elliot. 17 DR. DORFF: The other thing that Mr. Wiles 18 brought up in response to my question that I think we 19 at least need to think about, namely, as he put it, 20 that the FDA gave genetically modified foods a pass 21 without ever -- you know, so that Monsanto and so on 22 never have to demonstrate the safety of them. And I 23 think that's something that we at least should re- 24 examine in some way. 25 CHAIRPERSON MARSHALL: Mr. Cortezzi. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 275 1 MR. CORTEZZI: Ask and it shall be given unto 2 you. Seek and ye shall find. 3 [Laughter.] 4 CHAIRPERSON MARSHALL: So would it be the 5 committee's pleasure then to ask Mr. Cortezzi for our 6 next meeting that we have the materials? So a 7 background paper provided to -- 8 MR. CORTEZZI: Yes. The next meeting is in 9 October? 10 CHAIRPERSON MARSHALL: July. 11 MR. CORTEZZI: Oh, July. Okay. 12 CHAIRPERSON MARSHALL: End of July 13 MR. CORTEZZI: Yes, all right. 14 CHAIRPERSON MARSHALL: All right. Okay. 15 Thank you very much. I agree. We shouldn't sort of 16 run precipitously but we don't want to neglect an 17 important issue. 18 Abbey. 19 MS. MEYERS: I just feel that to be careful 20 on this issue in the absence of any human protections 21 at all that EPA -- not EPA, that at least -- at the 22 very least, that there a certification that each person 23 who volunteered has gone through the informed consent 24 process. I think at the very least that should be 25 something that they do for any information that's PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 276 1 submitted to them. 2 CHAIRPERSON MARSHALL: Any further 3 discussion? 4 [No response.] 5 CHAIRPERSON MARSHALL: All right. Then let 6 us -- well, timed, Dr. Koski, you made it for the 7 break. 8 [Laughter.] 9 CHAIRPERSON MARSHALL: We will break for 15 10 minutes. 11 DR. KOSKI: Timing in life is everything. 12 CHAIRPERSON MARSHALL: We will begin promptly 13 at ten after four. 14 [Brief recess taken at 3:55 p.m.] 15 CHAIRPERSON MARSHALL: We are going to go 16 ahead and start so that we can end on time. Felice, do 17 you have a -- 18 DR. F. LEVINE: Could I just take two seconds 19 to pass out the document that Susan and I did to revise 20 the confidentiality draft for NHRPAC so that we can 21 talk about it tomorrow. 22 CHAIRPERSON MARSHALL: Right. Yes, thank 23 you. Thank you very much, Felice, please do. 24 DR. F. LEVINE: Because I'm afraid that 25 people will leave. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 277 1 CHAIRPERSON MARSHALL: I'm sorry, you 2 mentioned that to me and -- 3 [Simultaneous conversation.] 4 CHAIRPERSON MARSHALL: -- fell through the 5 sieve-like memory that I have. Yes. 6 It was said earlier that we are not terribly 7 specific always in our discussions and I would like to 8 point out that in our update on informed consent that 9 Elliot is going to lead us in the discussion on -- oh, 10 terrible grammar here. 11 At any rate, we're going to be talking about 12 not one, not two, but three issues as explicated in 13 agenda. And I'm sorry that Mark is not here because we 14 have the perfect person to give us an exegeses on the 15 three issues. 16 [Laughter.] 17 DR. DORFF: I have a piece of paper here in 18 front of me that says two minutes, so I had better -- 19 [Laughter.] 20 DR. DORFF: That's called induced humility. 21 [Laughter.] 22 DR. DORFF: Okay. I have some good things to 23 report. The committee on informed consent has divided 24 into three. Well, what has happened is -- I mean, we 25 have done considerable work actually in the last two PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 278 1 months. We had, if you remember, just to remind 2 everybody, at our last meeting the committee had an 3 opportunity to meet and we had met by conference call 4 before the last meeting to come up with a list, a 5 preliminary list of topics that we ought to be 6 considering under the rubric of informed consent. 7 We were told ahead of time that there's a 8 separate workgroup dealing with informed consent for 9 the decisionally impaired, so that piece of it was not 10 part of our agenda. But we came up with a rather 11 larger agenda, and then during the course of the 12 meeting last time we had an opportunity to meet as a 13 committee together with other people who chose to join 14 that meeting and came up with yet a further list and 15 then at the meeting itself, remember, we came up with 16 yet a further list. 17 I played secretary and basically put all of 18 the various things into some kind of an order. And 19 then we had -- and shared that with the committee. We 20 had a conference call several weeks after the last 21 meeting in which what we tried to do was to prioritize 22 the many things that were raised. And what we decided 23 on during that conference call was that there were 24 actually three things -- three general rubrics of the 25 many things that we had identified as being important PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 279 1 in this area. And that we then created sub-workgroups 2 to deal with each one of these three things. 3 There will inevitably be some overlap, but we 4 are in any case starting with these three. 5 The first deals with the information. If we 6 are talking about informed consent, then the first part 7 deals with "informed" and what does it mean to make 8 sure that research subjects are in deed -- indeed have 9 the information that they need in order to be able to 10 make an informed decision. 11 The second workgroup is dealing with the 12 process of informed consent because one of the things 13 that we are all convinced about is that informed 14 consent cannot be reduced simply to documents, but 15 although documents play a role in it clearly, but that 16 the entire process needs to be examined in order to be 17 able to assure that there is indeed informed consent. 18 And the third group is dealing with voluntariness. The 19 consent part of informed consent. And, namely, the 20 various kinds of limitations on consent under various 21 circumstances and how to make sure that the consent is 22 indeed voluntary. 23 What has happened, once we had that meeting 24 is that each of the three subgroups has had the 25 opportunity to have a conference call to begin to do PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 280 1 its work. And the reason why we have not -- in two of 2 the three have actually produced very preliminary 3 documents, and the only reason why we haven't 4 distributed them to you is because of the preliminary 5 image just based on one conference call. 6 And the third group just had its conference 7 call last Thursday. So there's not even that. 8 So we are very much at the beginnings of this 9 process, but nevertheless, I mean, I think we have 10 helped -- we honed this. And I want to just 11 acknowledge right at the very beginning that Kate has 12 been absolutely wonderful in first of all helping us 13 organize ourselves, and in reminding us that we have 14 deadlines, and, you know, volunteers that we may be, 15 we're not supposed to work that way. 16 [Laughter.] 17 DR. DORFF: And I seriously want to thank her 18 for her help in organizing all of this for us. 19 So what I've asked -- is Cathy here? Cathy 20 Hannah? 21 MS. MEYERS: I don't see her. 22 DR. DORFF: Okay. I don't see her either. 23 Okay. So, Abbey, if you will. Abbey will talk about 24 what the first group did, the one dealing with 25 information. And then Judy will talk about the second PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 281 1 group, the one dealing with process and then I'll talk 2 about the third group, the one dealing with 3 voluntariness. Abbey. 4 MS. MEYERS: We were discussing the 5 understanding of the informed consent because there's a 6 big problem with understanding. And, of course, 7 everybody knows that the readability of an informed 8 consent document is very often a problem. But it's not 9 just the readability, the process of informed consent 10 is a process and it seems to be the informed consent 11 document itself is often treated like a contract or 12 another piece of red tape that investigators have to go 13 through. So a lot of things ought to happen and we 14 came up with some suggested solutions. 15 First is that maybe after the investigator 16 explains the whole thing to a person, they should take 17 that informed consent document home for a day or two 18 and speak to their clergy, their relatives, their 19 friends, and have a few days to digest it before they 20 sign it. 21 Second issue is perhaps it should be 22 videotaped so that the process itself people will feel 23 compelled to go through the process in the right way if 24 there's a videotaped record of it. 25 And then the third thing is that during the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 282 1 process, periodically, the investigator or whoever 2 gives the information to the subject should question 3 them like you would question a child, do you 4 understand, or what do you understand from what I just 5 said? And maybe then we'll get people to truly 6 understand. I think these things have to be done 7 because many times people will go through an 8 investigational process and when they're questioned 9 later, they don't even know that it was an experiment. 10 So it's very important that you're assured that they 11 understand its investigational during the informed 12 consent process. 13 DR. DORFF: Good. Thank you, Abbey. 14 I should have mentioned, I'm sorry, that 15 Cathy Hannah prepared for this working group a kind of 16 -- as she puts it -- notes from scanning the literature 17 so that she, you know, provided for us some of what the 18 literature has told us about conveying the information. 19 Among the things that she mentions here is 20 that in bioethics college have identified two distinct 21 standards for approaching the assessment of 22 comprehension of information. That is, what would be 23 understandable to a reasonable person -- to a 24 reasonable person, that's number one. 25 Or secondly that which would be PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 283 1 understandable to each individual patient. In other 2 words, an individually tailored approach. 3 And the literature also makes it clear that 4 things like level of educational attainment is one 5 issue that clearly arises in terms of whether the 6 information is understood, and another issue that she 7 raises from the literature is that the issue is not 8 just simply the ability to cognitively understand what 9 the person has been told, but to understand it. That 10 is, to be able to apply it to his or her own life. And 11 that consequently when we're talking about information 12 here, we're not simply talking about something that can 13 be sort of, you know, repeated on a test or something 14 like that. We are talking about much better kinds of 15 testing in which you actually try to apply the 16 information to the decision at hand. 17 And what Abbey was talking about, and this is 18 why I have to apologize to her, because I didn't put it 19 in the right context. What Abbey was talking about was 20 some of the ways in which the workgroup is trying to 21 figure out how you assess whether that kind of 22 understanding has actually taken place. 23 MS. MEYERS: Yes, I think that that was the 24 point of our conversation. That since the problem is 25 that the subject may not understand what this is all PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 284 1 about, that you have to find ways to test it throughout 2 the process and make sure before they leave the room 3 that they truly understand. 4 DR. DORFF: Shall we take these one by one? 5 CHAIRPERSON MARSHALL: It's at your pleasure. 6 DR. DORFF: Okay. So let's do that. Let's 7 talk now about information. Okay. Robert. 8 DR. RICH: Did you ever actually approach the 9 notion that an IRB should approve a quiz or something 10 with regard to the informed consent process? I've 11 heard that discussed before, you know, that a subject 12 is not actually informed unless they can provide 13 appropriate answers to 70 percent of some set of 14 questions or something. Was that an issue that you 15 discussed in your group? 16 MS. MEYERS: We didn't because we felt that 17 the informed consent process should be a conversation 18 on the level that the subject would understand. And to 19 go through something as formal as giving them a paper 20 and say, answer this true or false, would be too 21 artificial, I think, in that type of setting. And that 22 it's best to just stop after the first couple of 23 paragraphs and say, now, tell me what I just said. 24 Explain to me so that I know if you understand it. 25 DR. RICH: I wasn't suggesting a piece of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 285 1 paper, certainly. I mean, I think pieces of paper are 2 the real problem. The question is, should there be in 3 any kind of a formal process an oral iteration? An 4 oral iterative process that an IRB has looked into? 5 That's the question I'm raising. I have heard it 6 discussed. 7 MS. MEYERS: Yes, we didn't really discuss 8 that. No. 9 DR. DORFF: So, Abbey, if you would, take 10 that question back to the committee. 11 MS. MEYERS: Sure. 12 DR. SHAMOO: May I comment just on that? 13 Abbey, just make sure that we don't fall into 14 the trap where they are doing some of that kind of quiz 15 for schizophrenia research. They keep teaching them 16 the same material and it's the same test over and over 17 and over again until they get the required percent 18 passage and then they say, yah-hah, they understood. 19 That's like teaching a rat the same thing to do it over 20 and over. Just make sure that it is appropriate and it 21 is -- you get the outcome you are seeking. 22 DR. DORFF: Okay. I have Mary Kay then Mary 23 Faith and Sandy and Susan. I'm sorry. Okay. Bob. 24 All right. Mary Kay. 25 DR. PELIAS: Thank you. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 286 1 CHAIRPERSON MARSHALL: Your microphone is 2 still on. 3 DR. PELIAS: I have a serious question that 4 relates to the kind of information that you try to 5 impart and the population that you're trying to impart 6 information to. If we are in situations where we are 7 doing research with a large indigent population that is 8 to a great extent illiterate, you're going to have to 9 make some kind provisions for those folks so that they 10 can demonstrate some level of understanding. And my 11 experience with talking to patients like this has been 12 that they will agree to anything you say. Do you 13 understand? Yes, I understand. And then it should be 14 more than that. But you've got a basic problem with 15 people's whose education is extremely limited and who 16 will not understand, I'll bet, no matter what you do 17 for them. This is a difficult question. 18 Thank you. 19 DR. DORFF: Okay. Mary Faith. 20 CHAIRPERSON MARSHALL: I guess one thought 21 that I have in hearing about and reading about the work 22 of Jeremy Sugarman and others who have, you know, done 23 some empirical work in the area of informed consent -- 24 I mean, there's a huge, huge literature out there on it 25 -- is that there's an emerging new paradigm. I mean, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 287 1 we all know that informed consent is not an event, it's 2 a process and so forth. But that actually I guess the 3 new paradigm that Jeremy, who is on the working group, 4 espouses is that informed consent is really a 5 conversation and it occurs at every contact and 6 interaction between the investigator and the research 7 subject or participant and that it's really all about 8 decision-making on the part of the participant. 9 And so that rather than thinking that there 10 is a thing that happened sort of right up front that 11 involves what Tom Beauchamp would prefer to call a 12 disclosure document, not an informed consent form, that 13 this is something that is revisited in terms of the 14 patient's knowledge about what is happening now, what 15 went on before, and continued through a voluntary 16 participation that that happens at each encounter. So 17 that we really don't think about it as a one-event 18 model, but just sort of something that unfolds until 19 the research is over. And actually, you know, that 20 part of the proposal should be the investigator's plan 21 for disseminating the results of the study to the 22 research participant or subject and that that, you 23 know, sort of is perhaps and endpoint for this ongoing 24 conversation and decision-making process. 25 DR. DORFF: Sandy was next. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 288 1 DR. CHODOSH: I have a couple of concerns. 2 One, you mentioned videotaping the process. I think 3 that raises a whole bunch of other problems in privacy, 4 confidentiality, maintaining of such records, I just 5 envision a whole new area of problems. It's not a 6 problem for a lot of minor risk studies. It certainly 7 would be a problem for the kinds of studies where you 8 really want to know what happened in terms of 9 maintaining that kind of a file. You know, even if 10 it's on CDs, it's going to be a -- yes, you worry about 11 that. 12 My other is something I brought up at the 13 last meeting and that is that the idea of separating 14 these into two different kinds of functions, one about 15 the research and the other about all the legalistic 16 things that always have to be covered, but frankly 17 about which most subjects are not as interested in as 18 what's going to happen to me. They're not quite as 19 concerned down the road if I get injured because 20 somehow they think they will be taken care of. They 21 are concerned about are we going to have 15 needle 22 sticks in three minutes. That would concern them. 23 It would really make sense if -- we go 24 through this business that the comprehension is aimed 25 mainly at the research and that, yes, there has to be PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 289 1 some comprehension. But maybe we need to make that a 2 contract, the other aspect, make it a contract. You 3 know, if that's what people want, because that's what 4 the legal people at most institutions want, you know, 5 and just cover those items that clearly have some legal 6 implications for what will happen with that individual. 7 MS. MEYERS: Could I answer that? On the 8 videotape thing, all three of my children have been in 9 clinical research and all of them are videotaped when 10 they are given the informed consent. And if they 11 didn't want to go into research, it wouldn't be a 12 problem. But when they agree to go into research, part 13 of it is that they agree to be videotaped during the 14 process. And it's not going to be shown on TV, it's 15 kept in some vault somewhere. 16 DR. DORFF: Yes, I think what Sandy is asking 17 is, what are the privacy guarantees in regard to those 18 tapes? 19 MS. MEYERS: I would hope that they're the 20 same as the privacy guarantees for the whole thing, 21 your medical records and videotapes and whatever. 22 DR. DORFF: So that's one of the things that 23 the committee needs to at least mention; right? I 24 think that's his point. 25 MS. MEYERS: Uh-huh. Okay. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 290 1 And the second thing is, I really would 2 object to making a contract. I think that's been the 3 problem with informed consent over the last ten years, 4 at least, that they have proceeded to become a legal 5 contract. And many times I'll say to an investigator, 6 this informed consent is different than the one that I 7 saw six months ago. And they'll say, well, the lawyers 8 got ahold of it. And the lawyers are always putting in 9 legal things to protect the institution and it has 10 really eroded the effect of informed consent documents. 11 And I think that people are -- do care very much about 12 how much am I financially responsible for? What 13 happens if my insurance doesn't pay? What happens if 14 I'm injured and I have to come back into the hospital? 15 Who is going to pay the bill? They're very much 16 interested in that. 17 DR. DORFF: You probably have more than you 18 need on your plate, frankly, but one of the things I 19 would be interested in knowing is the degree to which 20 those kinds of documents actually do protect 21 institutions from legal suit. Given the fact that 22 everybody knows that they're signed without ever being 23 read, let alone understood. The real question is, what 24 have the courts done with these documents when push 25 comes to shove? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 291 1 MS. MEYERS: We only know about Jesse 2 Gelsinger and Ellen Roche, the two deaths that we've 3 heard about. So we don't really -- never went to 4 court, so -- 5 DR. DORFF: Okay. I have Susan, Bob, Alan, 6 anybody else? Oh, Mary Kay again, and Margaret. Okay. 7 MS. KORNETSKY: I have a couple different 8 comments and I don't know if they're specifically for 9 Abbey or for Judy or whatever because it sounds like a 10 lot of these things are sort of flowing from one group 11 to another. But whatever the workgroups do and I 12 understand -- I'm now being put on this group as well. 13 I think it's important to think, Abbey, about a 14 variety of methods and we talked a little bit about 15 this at lunch, that I'm very against sort of 16 proscribing one particular thing for assessing the 17 informed consent process. 18 There have been discussions about 19 ombudspersons in the informed consent process. We 20 actually had a situation where we tried that. We 21 wanted to try it. It was an AIDS trial and we ran into 22 all kinds of issues with confidentiality and having a 23 third party there. There are also limitations in 24 certain types of studies with testing. Afterwards, if 25 someone understands immediately after, do they remember PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 292 1 in a week, do they remember in two months? Does that 2 mean they weren't informed, does that mean informed, so 3 there are also limitations that are there. None of 4 these I'm saying that shouldn't be done, but I think 5 there's no one solution. 6 I think the other thing is, even looking at 7 ways of presenting information and helping people 8 understand. There have been some studies that use 9 videos to help provide information that people can take 10 home. There's also the format of the form. Things 11 like that are important to avoid over legalese type 12 things. There are flow charts, there's different types 13 of things within the process. 14 And I also really also speak to the fact of 15 what Mary Faith mentioned about it being an ongoing 16 process. I recently spoke with some nurses who get 17 consent in oncology trials and said to them, you know, 18 can you really truly get informed consent at that first 19 time and they said, there's no way that you can do 20 that. However, what their commitment was, every time 21 when the individual comes in to go over what's being 22 done, to remind them that it's voluntary and to have it 23 as part of the process continue as part of the trial. 24 And, lastly, there are other types of things 25 that can be done. If there are ways to have PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 293 1 individuals talk with other participants in research, 2 also educational types of efforts, helping individuals 3 understand the types of questions they should be asking 4 during an informed consent process throughout the 5 trial. So I'm not sure where these comments that may 6 go into many of the different groups, but I don't think 7 there's a one-size-fits-all and just the groups have to 8 be flexible. And I think what IRBs can use most are 9 some creative ideas and ways of thinking about it. 10 DR. DORFF: Bob's next. 11 DR. R. LEVINE: Thank you. The issue of 12 videotaping, that's been tried. There's one famous 13 study where people went through a very meticulous 14 informed consent process to open heart surgery and two 15 weeks later were questioned about the experience. Two- 16 third of them said there had never been any informed 17 consent, much less what the details were. 18 I don't think this is at all surprising. I 19 think that whenever we're called upon to make a big 20 decision, we take all of the information, we process it 21 one way or another, if you follow the advice that Abbey 22 just gave and which we at Yale also do, ask people to 23 take the consent document and the protocol to talk it 24 over with their doctor, their family, whoever they 25 consider a good consultant, at one point you have it PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 294 1 all together and you make your decision and then you 2 clear the circuits for the next decision. 3 I think earlier today somebody invoked the 4 memory of Ted Woodward. I want to invoke the memory of 5 Ted's son Bill who did a study at the Maryland State 6 Prison System where he found a way to get people to 7 remember the details of informed consent. He assembled 8 the prisoners, and he said, we're going to do some 9 research on an anti-cholera drug. And I'm going to 10 give this group a lecture and I'm going to come back 11 tomorrow and give you a test. And if you don't get a 12 passing grade on this test, you're not allowed to be a 13 research subject. 14 Not only did they all get a passing grade, 15 but they did better than the second-year medical 16 students in the pharmacology course -- 17 [Laughter.] 18 DR. R. LEVINE: -- I'm not finished. They 19 did better than his colleagues in the tropical medicine 20 department. Because they had a motivation, they wanted 21 to be research subjects. So we know a little bit about 22 what can motivate people to remember. What we don't 23 know is whether or not that's the most important aspect 24 of informed consent. 25 I think the most important aspect is PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 295 1 comprehension. And there are devices to measure 2 comprehension during the process. I'm not going to 3 bore you with the details now. 4 Finally, I want to say, there can be no doubt 5 about it that the purpose of the written document is to 6 protect the institution and the investigators against 7 the subject. The process is to give the subject or 8 prospective subject the wherewithal to protect her or 9 his own interest. But the document turns it around. 10 We do our best to create documents that also serve some 11 of the interests of the subjects. 12 Elliot asked, is there any evidence that 13 these things are good at protecting the interests of 14 the institution? To that I would respond that we've 15 been at it now since, let's say the late 1960s. So far 16 there has been no successful litigation at a reported 17 case level that people have failed to get informed 18 consent to research when the research has been reviewed 19 and approved by an IRB. And that can be contrasted 20 with, I would roughly estimate that there are 20 or 30 21 successful cases a week in the context of medical 22 practice. 23 One of the big differences is the meticulous 24 detail of the consent form and the presumption the 25 court usually makes is that if you looked at this piece PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 296 1 of paper, you should have understood all this stuff 2 before you agreed to go along with it. 3 I'm not saying that's evidence that we've 4 accomplished something that I think is wonderful, but 5 it is evidence that responds to your question, Elliot, 6 they are effective defenses if that's what we want to 7 create. 8 I've said enough. Thank you. 9 DR. DORFF: Alan. 10 DR. FLEISCHMAN: Elliot, the report that 11 Abbey gave us was from which of the workgroups? 12 DR. DORFF: This is on the informed part. In 13 other words, how do we make sure that information has 14 been transmitted? 15 DR. MORENO: Which means assessing. 16 DR. DORFF: That's right. Which has amounted 17 to -- which means assessing understanding. 18 DR. FLEISCHMAN: Okay. 19 DR. DORFF: In other words, that we 20 understand that it doesn't -- that it no longer means 21 just simply cognitive information, but that it means 22 comprehension or understanding. 23 DR. FLEISCHMAN: May I suggest that perhaps 24 you may need another mini-workgroup. And that is -- 25 [Laughter.] PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 297 1 DR. FLEISCHMAN: Hey, I didn't say you should 2 do it all at the same time, but on the content. 3 Because I don't see it here. Everything that you're 4 focusing on is process and assessing whether people 5 have heard something. But most IRBs are faced with 6 documents that are five, eight, 12 pages long. 7 Now some people talking about executive 8 summaries of documents which, you know, kind of sounds 9 a little strange. But, I think we need to come to 10 grips with that in this whole question of informed 11 consent as to how much is too much, and, you know, what 12 is the appropriate reasonable amount that would be both 13 reasonable and ethical and legal. 14 Second comment, I want to add to Mary Faith's 15 comment. I think we have in the information explosion 16 a great opportunity to do what I think a lot of people 17 have begun to call it continuous informing, or 18 continuous information delivery. By that I mean the 19 process of informed consent can continue throughout the 20 entire study. I think that's really what Mary Faith is 21 talking about and that we ought to be developing new 22 and innovative methods of informing subjects and 23 continually informing subjects. And even subjects who 24 don't have computers at home will be back to the 25 clinic, will be back to the academic center and will be PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 298 1 able to use those materials. And I really think we 2 could do a service by thinking about how to study the 3 effectiveness of these things. 4 I'm very nervous about prescription, like 5 Susan. These are all questions that can be empirically 6 studied as to whether at the end of the day or at the 7 end of the week or the end of the six weeks we will 8 have done any good before we prescribe. So one of the 9 things the informed consent workgroup may come out with 10 is a challenge to NIH or others to come up with 11 research RFPs to look at some of these questions that 12 we might help them lay out as we, you know, begin to 13 think about some of these alternative methods to do 14 this work. 15 DR. DORFF: I have Margaret and then Mary 16 Kay, and then I wanted to say something, and the 17 Felice. Okay. 18 Oh, I'm sorry, Kate, go ahead. 19 MS. GOTTFRIED: Just two points. One in 20 relation to what Alan just said. Are you talking then 21 again, not being too prescriptive but sort of coming up 22 with a guideline for a generalized inclusion criteria 23 of what ought to be in the informed consent. 24 DR. FLEISCHMAN: You know, I guess I was 25 talking about two different things at the same time so PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 299 1 I wasn't clear. One is I think yes, we need to talk 2 about the content and the inclusion criteria. And 3 second, apropos to the process and ascertainment of 4 whether people are understanding what's going on. I 5 think we need to think about that in a non-prescriptive 6 way that can be studied. 7 MS. GOTTFRIED: Right. Okay. And the other 8 point, just so when you talked about sort of an ongoing 9 iterative process, that is something that came up in 10 another mini-workgroup that Judy will report on. 11 Because that is something -- that group is focusing on 12 who ought to be engaged in the process of obtaining 13 informed consent and one of the issues raised was in 14 fact how ought the process ought to be conducted and 15 should it be in an ongoing basis intermittently 16 throughout the life of the protocol. 17 DR. DORFF: Okay. Margaret. 18 MS. BORWHAT: A lot of the comments have 19 already been said, but briefly, I would like to 20 reinforce Abbey's position that the documents be able 21 to go home. I know a lot of people make their decision 22 based on the influences of their family member and in 23 fact are inclined to perhaps change their decision. I 24 think they should have access to the full protocol. 25 And I would suggest that perhaps audiotaping might be PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 300 1 easier especially for those with limited funding, they 2 would be able to bring that home and use that at home. 3 And if they didn't have a particular device, that's at 4 a cost point where it's cheap enough for people to be 5 able to provide that, lend that to them for them to 6 bring it home and use it at home. 7 DR. DORFF: Mary Kay. 8 DR. PELIAS: Thank you. I'd like to throw 9 another wrinkle into this which is going to create 10 another series of headaches and that is how state 11 legislatures have dealt with this problem of consent 12 and the question of protecting the interests of the 13 institution as opposed to the subjects or the patients. 14 Some state statutes, for example, create a presumption 15 in their dealing with informed consent. They create a 16 presumption that in individual subject's or patient's 17 signature on a document is -- that the individual's 18 signature implies an understanding of everything in the 19 document. So if it goes into court, the presumption 20 is, with the signature that the individual subject or 21 patient understands everything. And then if it goes a 22 step further, and the patient or the subject decides to 23 take an issue to court, feels that he or she has been 24 wronged, the burden of the proof then shifts from -- it 25 shifts to the plaintiff or the subject who may have PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 301 1 very little understanding of what is going on, but is 2 then saddled with the burden of the proof. 3 And this is not the only state statutory 4 approach to it, but I think it's something that needs 5 to be at least acknowledged and that not only 6 acknowledged but that there are different state 7 approaches to this problem as well. Thank you. 8 MS. MEYERS: Yes, I think that that's a 9 question that we have to look at in a lot of issues 10 that we're dealing with whether the state law should 11 take precedence over the federal law. And since a lot 12 of the informed consent process is put back into local 13 control, I would assume that some state laws would 14 override it. But we would need our lawyer to figure 15 that one out and what should be recommended. 16 DR. DORFF: Okay. I have Felice and then 17 it's my turn and then Jonathan. 18 DR. F. LEVINE: I sort of had a responses at 19 a variety of levels. And I think, Abbey, that you're 20 kind of cutting into this in useful ways. I think that 21 we -- it seems a threshold question is what do people 22 need to know to make an informed decision and then how 23 to engage in that process in a way that indeed permits 24 an informed decision, reduces social desirability 25 responses, and other kinds of noise that affect and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 302 1 provides information in a concise and accessible way 2 and tells them indeed what they need to know and not a 3 lot of things that perhaps they don't need to know. 4 I the emphasis on it being a continuous 5 process is an important one. It also is a developing 6 process. At different stages you may need to know 7 certain things that you don't need to know at earlier 8 stages depending upon where you are at. 9 I think for me the biggest challenge for the 10 working group, and I want to say this as a colleague 11 scientist and researcher and citizen, not as a social 12 scientist at this table, and that is, how do we have -- 13 it's a challenge with all of our groups, but I think 14 this -- there's no issue that's more important than the 15 consent. 16 I mean, I know we've got two working groups 17 and this one is a big and important one and yet both 18 the expertise of the working group and our expertise is 19 largely both health of which actually a lot of my own 20 is largely both health and clinical. And so the 21 conversation unfolds with just a very narrow piece of 22 the pie Susan started mentioning. We need to look at 23 different methods of inquiry, different topics. We're 24 talking about how, of course, the regulations reaches 25 all forms of research. Research in educational PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 303 1 settings, work settings, in different countries and 2 cultures, in families at home, on the street, and yet 3 not -- the direction in which we're thinking about 4 perfecting and enhancing is really a very critical but 5 small piece of that pie. So I'm very interested in how 6 we elaborate the consideration of this issue to embrace 7 the various topics and nature of inquiry. I'm going to 8 stick away from fields of science; methods, topics of 9 inquiry. 10 Also we're talking about intervention. 11 Remember, it's also interaction. And so that we need 12 to be thinking about work where there isn't an 13 intervention, but where there's an interaction. We use 14 the language every time the subject comes in, well, a 15 vast amount of research the subject isn't coming in at 16 all. The researcher is going out. Or the research is 17 going out. 18 Just this past week I received two surveys in 19 the mail. It must be national survey week. 20 [Laughter.] 21 DR. F. LEVINE: One approaching me on -- 22 luckily I could say I wasn't a forensic psychologist. 23 I guess I was one once in may last life. So I was able 24 to check that off. But, indeed, a lot of work 25 approaches and reaches people in a variety of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 304 1 distributional mechanisms. 2 And so I think the biggest challenge, or one 3 of the biggest challenges for the informed consent 4 working group and the three areas is how to address the 5 range of context of research and the range of modes of 6 inquiry. And I'm very interested in us getting a jump 7 on this because I think it could be a terrific paradigm 8 for what we want to do more generally in the code and 9 that we have to get that jump early on in any way that 10 we can help do that. 11 DR. DORFF: I have myself down next on the 12 list. I have two things. One is that it occurred to 13 me that there are people whose professional expertise 14 is how you educate. And we probably ought to be 15 contacting some professional educators as to how you go 16 about gaining understanding. Because, you know, 17 because they might have some very good ideas as to how 18 to go about doing this. 19 The second thing that I wrote down, I 20 remember when I was on the way here, when I was reading 21 Cathy's point, is that we have to be careful -- we have 22 to be clear about the goals of getting this information 23 in the first place. One is to -- I'll tell you three 24 that came to my mind. And I don't know that all these 25 three goals are valid, but I think that if -- and I PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 305 1 think that the goal should determine the way that we 2 get the information. 3 One is to provide autonomy. Right. In other 4 words that we value the individual making decisions for 5 herself or himself and that therefore we have to give 6 the person enough information to be able to make a 7 decision. 8 Second, is to -- a second goal would be to 9 avoid assumed risks. In other words, the reason why we 10 are imparting information is because there are some 11 dangers involved in what we're about to do and we have 12 a duty to try, first do no harm. We have a duty to try 13 to protect people from harms and so if they are going 14 to be assuming certain risks, then we have to at least 15 warn them. And third, a third goal behind providing 16 information is to produce participation. And so -- I 17 mean, after it's all said and done, what we're 18 interested in is having research on human subjects so 19 that all of us can ultimately gain from that research. 20 Now, to that extent, the question then 21 becomes, well, don't we have -- I mean, we have 22 conflicting interests and on the one hand doing this 23 kind of human research and on the other hand, you know, 24 in which case we would not want to scare people too 25 much. And on the other hand, we want to make sure that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 306 1 they have enough information so that they can protect 2 themselves. 3 So, I mean, I think that in terms of the 4 information that's provided, it's the kind of thing 5 that you have in the clinical setting also where you 6 want to provide enough information so that people know 7 what are reasonable risks without telling them every 8 possible thing that might go wrong, which is, of 9 course, everything. 10 So, I mean, there's got to be some standard 11 by which we measure the information that is conveyed to 12 make it reasonable for these goals, but not overly 13 burdensome. 14 MS. MEYERS: One thing we did discuss, we did 15 discuss this whole thing about there is a presumption 16 that if the subject signs the informed consent that's 17 what's expected of them and it's like you win. And if 18 they walk out without signing it, it's like a failure 19 and that presumption has to be taken care of because it 20 -- the subject has not only every right to decline, but 21 you have to expect that many of them will and you don't 22 want to be biased against them because they did. 23 DR. DORFF: Okay. I have Jonathan, Adil, 24 Greg, Sandy. 25 DR. MORENO: I have a miscellaneous set of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 307 1 comments, but that seems to be the spirit of the 2 conversation. I don't think we should be too jaundiced 3 about how far we've come in the last 30 years. I mean, 4 there is one accomplishment in the several decades in 5 which people have been talking about this that I think 6 we ought to recognize namely that for the most part 7 people know they are in research when they are in 8 research. That was not the case so far as we can tell, 9 30 or 40 years ago, and that is really an 10 accomplishment. That's the first threshold you have to 11 get over. 12 The subject interview study that Jeremy 13 Sugarman ran for the Radiation Advisory Committee which 14 interviewed or surveys 1900 subjects in radiation 15 oncology, medical oncology and cardiology studies that 16 concluded that 92 percent -- 92 percent said that they 17 were in research and they were. Conversely, over 30 18 percent said they were in research and they weren't. 19 Which raises other interesting questions about people's 20 level of paranoia about these things. It's probably 21 healthier than we think, or at least higher than we 22 think. 23 An exception, of course, is procedures, 24 particularly surgical procedures which may well be 25 research and which are not called research in all PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 308 1 cases, but I'll leave that to another occasion. 2 Secondly, they are contracts, these forms, 3 they've always been contracts. In fact, it's only 4 since the pointy-headed ethicists and research 5 advocates, the human research subject advocates in the 6 last 30 years or less started worry about the 7 interpersonal relationship between the investigator and 8 the subject that there has been any concern about that. 9 And then there had been lots of ambitious statements 10 made by theologians and philosophers about how they 11 areal estate really co-adventurers in the process and 12 so forth. So in fact, in that respect also the 13 conversation has gotten richer than it was 30 or 40 14 years ago. So we've gotten a little further and we 15 shouldn't be too hard on ourselves. But it is -- 16 certainly there are lots of things we can do to move 17 things along, I agree. 18 I was surprised when Susan said that the 19 research ombudsman or advocate concept didn't fly in 20 Boston because -- well, the general clinical research 21 centers, as a number of people here know, have been 22 funded by NIH and there are about 75 GCRCs or CRCs, 23 each of them to have their own research subject 24 advocate and I think those people have just had their 25 first meeting. I know Greg was there, spoke to them. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 309 1 There is probably some information that we 2 should have as this work goes forward from that group, 3 perhaps two or three of them or some representative 4 person from that group of -- that's a group that's 5 actually going to be learning how to do this and 6 sharing information and so forth. And presumably they 7 didn't have a confidentiality problem. I don't know 8 why and I presume they're all medical staff and so 9 forth. So perhaps that's the reason it's not an issue. 10 The term, Elliot, that's often used to 11 distinguish between what is perhaps minimally accepted 12 cognitively and what we really would like, which I 13 think what you were talking about is from understanding 14 to appreciation. Appreciation being the level at which 15 we get to apply, we're able to apply our own values and 16 goals and quality of life, life plans, life objectives 17 to this decision. 18 I think we are in a funny position when we 19 talk about autonomy and then talk about making sure 20 that people can take it home to talk to everybody that 21 they know about this decision. And maybe somebody like 22 Felice can help us with this because really what we're 23 talking about is not autonomy or self determination in 24 some socially atomic way, but the reality that people 25 operate in families and communities and maybe your PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 310 1 group can advance the conversation by making it less 2 artificial with respect to how these decisions actually 3 get made. And maybe they're going to have to recruit 4 Felice or another social scientist to talk about that. 5 Finally, there's one, not only is it true as 6 Mary Kay mentioned that people are illiterate in their 7 problems with language, people are also enumerate. And 8 so how risks get communicated needs to be a topic, it 9 seems to me, not just what this is about, but how do I 10 -- how competently can people assess their chances? 11 One out of 100, well, that's me. So, should those 12 kinds of numbers be in forms? Lawyers do like to have 13 all the numbers that the investigators have in the 14 form, but those numbers need to be interpreted. And 15 there are a few people, not many, who are working on 16 how you communicate risk to people who -- to ordinary 17 folks and to people who even have less than the 18 standard capacity to understand what numbers mean. 19 DR. DORFF: Adil is next. 20 DR. SHAMOO: Thank you, Elliot. 21 When we talk about state/federal relationship 22 laws, I think I would recommend Jack Schwartz who is in 23 the Maryland Attorney General's Office and he was the 24 consultant for NBAC that we consult with him. He is 25 really an expert between state and federal relationship PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 311 1 when it comes to human research protection issues. He 2 has been involved in this issue for about six, seven 3 years. 4 Having said that, my understanding is that 5 state laws do not preempt federal laws unless the 6 federal law is embedded in it, a section saying that 7 they are allowed to do so. And that's rarely the 8 federal government gives that right to the states. And 9 furthermore, Mary Kay talked about that the states, 10 they may have a law, et cetera. However, going to 11 federal courts preempts that as it becomes the state 12 law, whatever they have said about informed consent is 13 irrelevant and some of these lawsuits have gone to the 14 federal court and some of them at least have been one, 15 at least one I know of has been one. 16 Furthermore, Bob Levine said about there 17 hasn't been that many cases in court about research 18 subject issues. 19 DR. R. LEVINE: [Off mic.] Bob Levine said 20 no such thing. 21 DR. SHAMOO: That's correct. Okay. 22 DR. R. LEVINE: [Off mic.] 23 DR. SHAMOO: Okay. You said what you said. 24 Exactly since I can't verbatim say -- none of here can 25 say verbatim exactly what you said. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 312 1 DR. R. LEVINE: [Off mic.] What you quoted 2 me as saying conveys different meaning. I don't mind 3 if you change the words, but not the meaning. 4 DR. SHAMOO: What is your meaning? Let's 5 make sure what is your meaning? You -- 6 DR. R. LEVINE: Almost no cases -- 7 DR. SHAMOO: Yes. 8 DR. R. LEVINE: -- when research has been 9 conducted according to a protocol reviewed and approved 10 by an IRB have been found against the investigators on 11 grounds of failure to get informed consent consent. 12 DR. SHAMOO: Okay. That was my correct 13 understanding despite what you said. Despite what you 14 said, there has been a case on dignitary harm in 15 Florida have been one in federal court. 16 DR. R. LEVINE: That did not get tried in 17 federal court. That was an out-of-court settlement, 18 $3.8 million. 19 DR. SHAMOO: Okay. I stand corrected. 20 Anything else? 21 DR. R. LEVINE: No. 22 DR. SHAMOO: Wait a minute. And having said 23 that, that the informed consent has been used as a 24 contract and I'll give you an example of that, the lead 25 case in Maryland has been sued based on negligence. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 313 1 And what I'm trying to say, the message is that there 2 may have been a lot of cases where it is research 3 except lawsuits have been on negligence, medical 4 negligence because there is a huge amount of court 5 cases and it's easier for them. And the case in 6 Maryland that is the basis of it is negligence, medical 7 negligence, not research subject issue. 8 DR. R. LEVINE: What you say is correct, but 9 utterly unrelated to anything I said. I'm talking 10 about informed consent. 11 DR. DORFF: Okay. We need to go to Greg and 12 Sandy and then I want to ask Judy to talk about 13 subgroup two. 14 DR. KOSKI: Elliot, I want to just take issue 15 with one of the things that I thought I heard you say 16 and that is that one of the goals of the process of 17 informed consent was to gain participation. Now, that 18 may, in fact, be the case in the way that it has been 19 conducted, but I would argue that conceptually, and 20 perhaps attitudinally that's flawed because in fact, I 21 think I mentioned this in the last meeting when we were 22 talking about this, the very use of the term, informed 23 consent, implies an outcome of the process that in fact 24 leads us down a road that is not really where we want 25 to go. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 314 1 The goal here is to help the individual that 2 we're asking to participate to make an informed 3 decision. And, indeed, if you put this process into 4 the context of a continuing process, informed 5 participation would be something that we would want to 6 achieve. So I'm just cautioning the use of the words 7 and the -- again, the approach that is taken is one 8 that we need to be careful about. Because the notion 9 of trying to use the process to gain participation, in 10 fact, may be contrary to the desired outcome. 11 DR. R. LEVINE: Let me make a comment on that 12 point. That the original term was voluntary consent in 13 the Nuremberg Code. The reason that it was replaced in 14 1957 by the word "informed consent" was curiously as a 15 result of an amicus brief filed by the American College 16 of Surgeons who on this occasion were opposing the 17 whole idea. But they persuaded the judge that 18 "informed" was the same as "voluntary" and here we are. 19 DR. KOSKI: Well, I guess my point, Bob, is 20 that I would hate to see the group get somehow trapped 21 by it's own words in terms of where that leads you with 22 respect to process so that again, moving away, even as 23 we said, to the notion of informed decision-making, 24 informed participation or voluntary, whatever, is 25 something that, again, helps us get beyond the box that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 315 1 we're currently in. 2 DR. DORFF: Greg, I agree with you, that's 3 the reason why I said of the goals. I'm not completely 4 sure that all of them are good goals, but these are the 5 kinds of things that people might have in mind when 6 they think about this. And what you're saying is 7 right, I think, that the last of those goals that I 8 mentioned is problematic. I think you're right about 9 that. 10 Sandy. 11 DR. CHODOSH: I just want to come back to 12 something that Felice mentioned and it's something that 13 apparently has not been considered. And that is, I 14 guess I've obtained or been involved in obtaining 15 consent from several thousand subjects over my career. 16 In most of those they were in studies studying acute 17 pulmonary infection. You can't send someone home for a 18 day to think about are you going to -- you know, do you 19 really want to do this because that's unethical. So 20 that there are some special concerns that have to be 21 taken into consideration in all kinds of emerging 22 situations where you must start something right away. 23 So, therefore, special care needs to be taken in how 24 you obtain consent in those situations. 25 Now, fortunately, most of these situations PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 316 1 are those in which, quotes, the subject is going to get 2 some kind of treatment. It may not be considered to be 3 -- I know some people are purists and say, that's not 4 treatment, but indeed it is treatment and they know 5 that and it does sway them. So you have to be careful 6 that that is not the predominant feature of why they 7 say yes. But that has to be in there. And there are a 8 lot of emergency situations where you can't get 9 conformed consent. 10 DR. DORFF: Okay. We move now to subgroup 11 two. Judy, if you would. This is about the process. 12 DR. SIEGEL: A lot of what I'm going to say 13 has actually been said. I'm going to say it anyway, 14 again, but with a different twist, hopefully. 15 [Laughter.] 16 DR. SIEGEL: I just want to read what I think 17 is how we understand what the question is to our group 18 which is in the larger context of issues around gaining 19 informed consent. There is a question of who should be 20 involved in the informed consent process and help bring 21 the research subject to the point of initial consent 22 and continuing consent thereafter. 23 So that's the sort of general -- again, 24 continuing on the question, it is assumed that the 25 informed consent process is in place to educate the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 317 1 subject about the research study for which they are 2 volunteering to insure that they have been given all 3 the information about the study, what's generally 4 included in the informed consent form, but we would 5 also go on to say, and also outcomes during the 6 research process so that they're getting all of the 7 information and that they understand the possible risks 8 to themselves engendered by participating in the 9 research, et cetera, et cetera. 10 The process of informed consent does not end 11 with the signing of the informed consent form and it is 12 the responsibility of the investigator or whoever to 13 ensure that the subject continues to remember and 14 understand the elements of the research and continues 15 to agree to participate. So I think that's sort of the 16 context in which we're talking about who should be 17 giving informed consent. 18 What we've done is we've listed sort of an 19 overview of varying points that discussions with 20 potential participants and participants occur from 21 initial screening that may be phoned into a phone-in 22 number all the way through the treatment phase of the 23 study and to the end of the study. And we've asked 24 some questions about who is, should be, or could be 25 involved in each one of those -- at each one of those PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 318 1 points. And some of the general questions are, what 2 issues about obtaining informed consent accrue back to 3 the person who is responsible for the discussion? 4 Examples are, is the person impartial and how impartial 5 does a person have to be who is having these 6 discussions with potential subjects or actually 7 subjects who have already consented to participate? 8 Does the person who is actually having these 9 discussions adequately understand the study and the 10 issues that the person who is actually being asked to 11 participate have in participating in the study. Does 12 this person, whoever they are who is engaging in this 13 discussion with the subject have the skills to 14 facilitate a good informed consent discussion? And I 15 don't think we've actually talked about what those 16 skills actually might be. 17 And then, in general, does the IRB or the 18 investigational site or whoever is involved really 19 understand what is involved in a good informed consent 20 discussion and how to maintain it throughout? 21 We also then sort of talked about, well, what 22 are the potential problems for a subject if the wrong 23 person is giving informed consent and what are some of 24 the risks? And then who should be involved and why? 25 So, again, we have this whole laundry list PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 319 1 that we can apply to various points during the consent 2 process. To someone's point before I actually had a 3 very nice back and forth of e-mails with Jeremy 4 Sugarman saying, well, we've laid out the questions, 5 can you help point me -- sort of chairing this about 6 the literature I should go to. And his comment back to 7 me, Mary Faith, was, "this was huge" big letters. 8 [Laughter.] 9 DR. SIEGEL: You know and so one of the 10 questions that I would like to ask as we sort of start 11 to put this together is, this could be a huge document. 12 This is at least a framework for maybe asking some of 13 the questions and how far into the literature or to 14 Alan's point do we actually need to get some more 15 research on this, do we actually want to go to put this 16 together? 17 DR. DORFF: Okay. 18 MS. GOTTFRIED: Well, in partial response, I 19 had thought about that some and I did have occasion to 20 touch base with Jeremy as well recently about this 21 particular issue and how extensive it is. And one of 22 the thoughts that I had in talking with him was in fact 23 commissioning a paper by somebody with particular 24 expertise in this area. And he was going to think of 25 some names and get back to me shortly. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 3 20 1 The other thing is, I think, Susan, it might 2 be useful for you to mention what you said about your 3 attempt to get some access to the NIH monies and what 4 your institution is endeavoring to do. 5 DR. SIEGEL: Well, we don't have the funding 6 yet. But we are -- our institution is applying for 7 funding as many institutions are for money from NIH 8 that's available. And what we have thought about doing 9 is to hire someone for a year's period of time at our 10 institution to really, number one, go through the 11 literature about the informed consent process, what is 12 known and to do something like that. But then to 13 really spend time within the institution speaking with 14 lots of investigators, lots of research nurses, lots of 15 subjects who could be in focus groups, interviews, or 16 whatever, really to come up for our institution. The 17 purpose is for our institution within pediatrics about 18 some guidelines about ways that we can improve the 19 process and in how we can evaluate whether that 20 improvement is taking place. 21 So that was, you know, some of our ideas. It 22 may or may not be funded, and if it is, we'll be doing 23 something during the next year, hopefully. 24 DR. DORFF: Okay. Let me just take Alan and 25 then -- okay, go ahead. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 321 1 DR. FLEISCHMAN: Judy, could you unpack this 2 concept of impartiality a little bit? I had never 3 heard that suggested and I've certainly never seen it. 4 So where are you going with that? 5 DR. SIEGEL: Well, I think the whole 6 discussion of is the investigator the appropriate 7 person to actually have the discussion? And there's, I 8 guess, a certain group that says, well, maybe in fact 9 the investigator is the only one who can adequately 10 explain what is about to happen and then there is 11 another group that says, and, in fact, they may really 12 believe in this and be sort of overly. So that's what 13 I meant by impartiality. 14 Us there a way to get the appropriate 15 information, which may be very detailed and complicated 16 to someone one without sort of pushing in the direction 17 that says, I really believe in this and so I want you 18 to -- you know, to Elliot's point, you know, are we 19 pushing people to participate in some way? 20 DR. DORFF: Okay. Kate and then I'm just 21 going to describe to you very quickly what the third 22 group has done and then Bob is on for 15 minutes, I 23 understand and then we're going to break. Is that 24 right? 25 MS. GOTTFRIED: Right. Alan, also it sort of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 322 1 follows up on the issue that I think also came up in 2 the children's workgroup to some extent, the notion 3 that sort of an ombudsperson who would be sort of 4 divorced from the process, per se, the protocol, and 5 could ensure that there is a more objective, unbiased 6 process that unfolds so that we're obtaining, 7 quote/unquote, "informed objective consent." And this 8 came up, I believe, at the hearing, also where -- was 9 it Shirley McThias, I think brought this issue up at 10 the hearing as well, and I heard this at a meeting I 11 was at recently too where thee's a request that there 12 be some sort of process built in for some sense of 13 impartiality, whether that would be in tandem with 14 someone from the protocol team who might be required 15 because of their expertise, et cetera. 16 DR. FLEISCHMAN: I just think it would be 17 important to separate out the concept of consent 18 monitoring which has been talked about and written 19 aboiut, and creating a kind of new standard of 20 impartiality of informing. That's a -- I mean, I'm not 21 opposing it. I'd be interested in hearing more about 22 it. But I think it's a very radical -- radical meaning 23 different, not radical meaning bad -- but very 24 different approach. And I think, you know, it remains 25 to be seen how that gets sorted out. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 323 1 MS. GOTTFRIED: Right. 2 DR. SHAMOO: Elliot, just on that point. We 3 have proposed probably, Alan, you know, for about six, 4 seven eight years that there be an independent 5 physician or independent professional who is 6 responsible for advising the subject whether it should 7 -- 8 PARTICIPANT: [Off mic.] 9 DR. SHAMOO: No, should subject -- this came 10 up when we were talking about psychiatric research 11 because the psychiatrist have such a relationship with 12 their patients that it could be coercive when that 13 psychiatrist says, here is the type of research I want 14 you to enroll and you, blah-blah, you could benefit 15 from it. And that's the context it was put into. And 16 the 1998 NIH points to consider proposed that was one 17 of the points for consideration for the research 18 community in the mental health field. 19 And I'm sure Bob is going to find something 20 wrong in what I said. 21 DR. CHODOSH: Oh, just along those lines. 22 Are we talking about a professional witness? I mean, 23 you know, we talked about using witness signatures. 24 Are we really talking about a professional witness, or 25 whatever you want to call it? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 324 1 DR. DORFF: It's something for you to think 2 about, Judy. 3 DR. SIEGEL: Right. 4 DR. DORFF: Okay. Let me just tell you about 5 the third one, just very briefly. The third group had 6 its first conference call last Thursday based upon a 7 paper that Skip Nelson had prepared for the VA 8 conference on informed consent in March of 2001. And 9 based upon that we raised two primary questions. The 10 first question is the one thing that we want to get to 11 is some kind of conceptual clarity as to what we mean 12 by "voluntary." And here all of the literature in the 13 philosophic world about free will and all of that will 14 come to the fore. 15 Skip, himself, in the paper uses the 16 definition of a voluntary choice in Black's Law 17 Dictionary which is, "unrestrained by interference, 18 unimpeded by another's influence, spontaneous acting of 19 ones self, done by design or intention, preceding from 20 the free and unrestrained will of a person." As usual, 21 when you have that many clauses you're in trouble. 22 One of those clauses is "unimpeded by 23 another's influence." Well, of course, every single 24 one of our choices is impeded by other people's 25 influences. I mean, maybe even vanilla, chocolate or PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 325 1 strawberry. So the thing is that it's a -- and it 2 should be mint chocolate chip anyway. So anyway what 3 we are after is -- if not cherry garcia. Anyway, what 4 we are after is conceptual clarity. Okay. As to 5 exactly what we're talking about when we're talking 6 about voluntary. To what extent -- when do the various 7 influences that lead a person to decide X as opposed to 8 Y become undue influences? That's really what we're 9 after. 10 And then the second question is, how do we 11 measure voluntariness? It's hard enough to measure 12 information. That's the kind of thing that Abbey was 13 talking about and conveying of understanding and 14 appreciation. But how do you measure voluntariness? 15 Now, obviously there are some populations 16 where that's especially an acute concern like 17 prisoners, or people, or the decisionally impaired, 18 that's another group though. But even if you're 19 talking about people who are mentally competent and who 20 are not under any particular restraints that we can 21 tell, that we can identify, how do you know when, you 22 know, the person is actually choosing this of his or 23 her own volition and when not? And how do you measure 24 that. So those are the two primary things that we 25 wanted to talk about. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 326 1 Okay. We are already over because I guess 2 Bob has been promised 15 minutes and so if you would. 3 DR. R. LEVINE: Do you want me to speak from 4 here? 5 CHAIRPERSON MARSHALL: Why don't you come up 6 here, Bob. 7 DR. R. LEVINE: I'm hoping I won't need the 8 entire 15 minutes. I'm not as well prepared as I wish 9 I was and that's because all of the contents of the 10 hard drive of my computer vanished recently. 11 CHAIRPERSON MARSHALL: His dog ate the 12 computer, I think is the story. 13 DR. R. LEVINE: I beg your pardon? 14 CHAIRPERSON MARSHALL: The dog ate your 15 computer. 16 DR. R. LEVINE: The dog ate my computer. I 17 don't know, I think it was a dragon, actually, the 18 Dragon Naturally Speaking program. But I don't know 19 about that. 20 What I'm going to do is give a report of one 21 of the subcommittees of the subcommittee that's headed 22 up by Felice Levine and Jeff Cohen on the 23 interrelatedness of social behavioral research to the 24 -- or special problems in social and behavioral 25 research as regards protection of human subjects. And PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 327 1 more particularly I'm going to talk about the problems 2 with informed consent and consent forms in the 3 mainstream of social and behavioral research. And this 4 is based upon a report that was draft by Joan Sieber 5 and me. Joan couldn't be with us today, so I will 6 present it. 7 It's a long report. It would take me much 8 more than 15 minutes to read it, so I'm just going to 9 pick out a couple of the highlights of the report. 10 For those of you who don't know, I'm not a 11 social scientist and I'm not a behavioral scientist. I 12 am by training and inclination a natural scientist, a 13 clinical pharmacologist. 14 The biomedical focus has always posed 15 problems for social and behavioral research since it 16 set a default condition that was generally 17 inappropriate to social and behavioral research. These 18 problems existed even in the 1970s through 1990s when 19 most IRBs more loosely interpreted the regulations in 20 ways that were generally not unduly restrictive of 21 social and behavioral research. 22 More recently things have taken a drastic 23 turn. There has been a great concern around the 24 country amongst IRBs that they be very, very careful to 25 require anything that it might seem anyone else might PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 328 1 consider would be required. In large part this has to 2 do with the reports of various university research 3 centers being closed. And when the reasons or what 4 people read as the reasons for these closures appear in 5 the newspapers, there's been a great concern about 6 making sure that these errors were apparent errors were 7 not repeated. 8 An important example of the nature of the 9 problem is the very surprising interpretation of the 10 definition of "human research subject" that gave us 11 what we have been calling the "third-party issue." 12 Now, for this reason, many IRBs in their 13 effort to go by the book require a signed consent form 14 even when this would be highly disrespectful of the 15 subjects. For example, in cultures in which persons 16 are illiterate or do not believe in signing documents, 17 more generally within the mainstream western culture 18 Singer and Trice have found that a significant number 19 of subjects will refuse to participate even in surveys 20 or in studies and experiments if required to sign a 21 consent form, but would otherwise very gladly 22 participate. The studies that I'm most familiar with 23 are those of Eleanor Singer who shows a very 24 substantial reduction in people willing to participate 25 even if after they finish their participation if PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 329 1 they're asked to sign a document authorizing it. 2 No kidding. They say, you're not allowed to 3 use my data. 4 Most social and behavioral research presents 5 no more than minimal risk. The statement, quote, "no 6 procedures for which written consent is normally 7 required outside of the research context" is stated 8 with reference to medical procedures. 9 Consent forms are not used to document the 10 patient's willingness to be interviewed or to complete 11 questionnaires. To cut to the bottom line here, our 12 group would like to present the argument that if we 13 apply the same standards to social research as are 14 applied to biomedical research, that it's rare that 15 social research gets much more invasive or threatening 16 than what's asked in a routine family history during a 17 routine medical examination. And this then is one of 18 the criteria for waiving the requirement for 19 documentation of consent. 20 In the current regulatory climate many IRBs 21 treat social and behavior research as if it were very 22 risky. The focus on very minor or unlikely risks has 23 resulted in lengthy negotiations between IRBs and 24 investigators and overly detailed, insultingly 25 paternalistic, informed consent procedures. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 330 1 That's our preamble. I want to go and read 2 excerpts from the specific recommendations. 3 Recommendation one. Informed consent should 4 take the form of an open, easily understood 5 communication process. Typically this means a friendly 6 verbal exchange between researcher and subject. 7 Instead of having a consent document for most 8 encounters where the subject and the researcher 9 actually meet, there should be an information sheet. 10 This would be designed to uphold the interests of the 11 subject and the only person to sign it would be the 12 researcher and the subject would be given the copy. 13 Another point against using written documents 14 in lieu of consent discussions is there's been an 15 extreme focus in recent years on the readability level 16 of consent forms. Those IRBs who do this usually are 17 striving to accomplish a sixth grade reading level. 18 What they seem not to pay attention to is that in our 19 cities as many as 25 or 30 percent of the subject 20 population can't read at any level. When you rely on 21 the document then you are completely leaving out those 22 people who are less literate than a sixth grade reading 23 level. 24 The second recommendation, if there may be 25 risk of harm or inconvenience to certain subjects, it PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 331 1 is important that subjects receive enough easily 2 understood information to judge whether the risk is at 3 a level they can accept. I trust that that's non- 4 controversial. 5 The third one is that the subject should be 6 informed very clearly that they're free to ask 7 questions at any time. But they should always take 8 into account the context of the research. 9 As Felice pointed out earlier, sometimes the 10 investigator and the subject never meet. But even in 11 these conditions, the subject can be provided with a 12 telephone number to call in case they want to ask some 13 questions. 14 Number four, when the subject can readily 15 refuse to participate by hanging up the telephone or 16 tossing out a mailed survey, the informed consent can 17 be extremely brief, often stated in one or two 18 sentences. 19 Number five, verbal informed consent need not 20 be detailed and written consent is not appropriate when 21 the research is not concerned with sensitive personal 22 information and when the subjects are peers or 23 superiors of the researcher. This is what the social 24 scientist will refer to as studying up rather than 25 studying down. And this is one of two recommendations PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 332 1 on that point. 2 Number six, the cultural norms and lifestyles 3 of the subjects should be considered in deciding how to 4 approach informed consent. This is something that's 5 been incorporated in the CIOMS international ethical 6 guidelines since 1993 where it's conceded that the 7 typical American IRB can't possibly understand what 8 counts as private information, what counts as informed 9 consent, what counts as undue inducement in the many, 10 many cultures that have elaborate gift exchange 11 traditions and so on. So what we are hoping is that 12 somehow the system can be set up so that people who are 13 in a decision-making position can make their decisions 14 based upon a true knowledge of the cultural norms and 15 lifestyles of the actual subject population. 16 Number seven, IRBs should be flexible in 17 considering a wide range of media for administering 18 information. This could include video tapes, 19 brochures, group discussions, web sites, community 20 newsletters, and Joan would also rely on the grapevine 21 in a way that I must learn how to understand a bit 22 better. That's the only difference that Joan and I 23 have in this document at this point. 24 Number eight, when written or signed consent 25 to place the subjects at risk a waiver of the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 333 1 requirement for written documentation should be 2 considered. That's very close to what the current 3 regulations say except that we would take on step 4 beyond. The current regulations say, when the document 5 is the only thing that links the subject to the 6 research and confidentiality is the -- breech of 7 confidentiality is the only threat, we would go beyond 8 that and say, just because there's one link doesn't 9 justify creating yet another link to the private 10 information. 11 Number nine, to the extent that it may 12 enhance respect for and well-being of research 13 subjects, it may be desirable for the researcher to 14 consult with community representatives or leaders. And 15 in certain types of projects it might be of value to 16 engage in a full fledged community consultation. We 17 want to make it clear though that this recommendation 18 is not ever meant to provide a substitute for 19 individual and informed consent. It's just designed to 20 create a setting in which it's more clear that the 21 research has the understanding support of the community 22 and also to begin to educate the members of the 23 community about the research program before anyone's 24 approach for individual informed consent. 25 Here is another one that was controversial PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 334 1 within our group, but I hope we got it so that it's 2 less controversial now. In organizational research 3 conducted by an outside investigator not commissioned 4 by the heads of the organization it is essential to 5 obtain the superior's permission to study subordinance. 6 The clarification that we achieved during our 7 group discussion is, we're not getting permission to -- 8 the permission that we get from the so-called superior 9 is the permission to enter the institution. This does 10 not take the place of informed consent or the freedom 11 of particular individuals within the institution to say 12 yes or no. 13 I'm getting near the end. 14 Recommendation number 11, there are various 15 kinds of research that cannot be validly carried out if 16 all details are disclosed at the outset. The 17 alternatives to outright deception of subjects are: 18 one, to obtain permission to provide only a description 19 of what the subject will experience with an agreement 20 that the full details of the study will be disclosed 21 afterward. 22 Two, to obtain permission to engage in 23 concealment or deception with the understanding that 24 pilot research has shown that peers of the subject do 25 not find such concealment or deception objectionable PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 335 1 and that a full explanation will follow their 2 participation. 3 And third, and last, to explain that the 4 subject might be enrolled in one of several possible 5 conditions and to engage permission -- to gain 6 permission to enroll the subject in an undisclosed one 7 of these conditions to be disclosed in the general case 8 at the end of the research. 9 Number 12, in certain circumstances persons 10 are not in a position to decide whether to consent 11 until after their participation. This includes brief 12 sidewalk interviews which persons are likely to 13 welcome. Deferred consent is an option. 14 Thirteen, and I feel it necessary to say, 15 there will be a total of 14. 16 [Laughter.] 17 DR. R. LEVINE: Reminded of Tom Leher saying, 18 "you have yourselves to blame if I'm too long you 19 should never have let me begin." 20 Debriefing is an important and complex 21 understanding that is not always appropriate. I'm not 22 going to go into detail about that now. But I would be 23 willing to discuss some circumstances in which 24 debriefing would not be appropriate. 25 And then finally, another one that's somewhat PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 336 1 controversial within our group. Elite interviews. And 2 by that we refer to interviews with important persons 3 or experts or what the regulations refer to public 4 persons. Typically these are open-ended and defer to 5 the expertise of the respondent to direct parts of the 6 dialogue. Such respondents are rarely low powered 7 persons and some of the usual trappings of informed 8 consent may be seen by these respondents as too 9 paternalistic to be appropriate. 10 In the remaining 30 seconds, I'll be glad to 11 respond to your questions. 12 CHAIRPERSON MARSHALL: Felice, and brief. 13 Yes, we really need to stop. 14 DR. F. LEVINE: Less of a comment, just a 15 little overview of the process of where we are. Our 16 group -- in part, these were two working papers that we 17 started on as early as last July that then were knitted 18 into one well before an informed consent group was 19 established. And our group has continued that 20 deliberation. 21 We met either virtually or face-to-face 22 depending upon who was there on the 22nd and now we've 23 discussed the full report and the recommendations and 24 what our anticipation is, is to rework them and advance 25 them as soon as we can to the informed consent group PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 337 1 which we think will be sooner than later, meaning 2 probably within the next several weeks. But we really 3 didn't have a chance. You could tell the tentativeness 4 is we didn't have a chance to rework each in light of 5 the conversation and that's sort of the process that 6 it's in now. 7 DR. R. LEVINE: Thank you, Felice. I was 8 willing to take the whole blame for that. 9 Susan. 10 MS. KORNETSKY: Yes, I guess I just had one 11 question. There wasn't, I don't think, any one of 12 those issues that I couldn't have agreed with in 13 certain types of research. This is for what? For 14 behavioral and social research in general, in certain 15 types? 16 I mean, how is this -- like I said, there's 17 nothing in there that I disagreed with in specific 18 circumstances, but how is that going to be communicated 19 with it? Because I can think of certain types of 20 behavior or social research where certain things would 21 certainly not be appropriate. 22 DR. R. LEVINE: I agree wholeheartedly. And 23 the purpose of this is to try to paint an 24 impressionistic picture of the whole field. And an 25 awful lot of what I said would tip over into some PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 338 1 research that is typically considered biomedical, but 2 uses similar devices, particularly such things as 3 epidemiology -- much epidemiology, not all 4 epidemiology. 5 Nothing I said applies to all social or all 6 behavior research. But everything that I said applies 7 to some more or less well-defined areas within those 8 two fields and some areas of biomedical research. 9 I think our job then will be to take a next 10 step and try to flesh out perhaps by giving examples 11 what we mean by all of this. 12 MS. KORNETSKY: I would definitely agree 13 because I think the harm is, you know, sending mixed 14 messages to the research community on when some of 15 these things are appropriate or not. So, I think you 16 need to somehow define when these types of things are 17 appropriate. 18 DR. R. LEVINE: I want to respond that -- oh, 19 I'm sorry. 20 CHAIRPERSON MARSHALL: Well, I just want to 21 say, I feel as though we're imposing on the good will 22 of the folks who are sitting in the room. So we really 23 need to sort of wrap up. If we need to revisit some 24 things tomorrow, then I think that we can. So brief 25 comments at the podium and then -- PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 339 1 PARTICIPANT: My question was whether we 2 could revisit this tomorrow because it was an enormous 3 amount of information that was imparted very quickly at 4 the end here. To go over 14 points at breakneck speed 5 and I'm a fast note taker, it just -- you know, was 6 just too much too late in the day. 7 And I guess I should just start with number 8 one which was simply that I cannot conceive that you're 9 saying that there should be no need for patient 10 consent, just give the signatures which was your very 11 first point, of the person who gives the patient the 12 sheet itself. There should be a friendly, open 13 exchange, but to remove the patient consent form and 14 just have the person that gives the information sign-in 15 sheet doesn't make sense to me. 16 CHAIRPERSON MARSHALL: Let me just explain 17 where we are in terms of process. 18 PARTICIPANT: Sure. 19 CHAIRPERSON MARSHALL: This is very 20 preliminary. This is for information only. So we -- 21 it hasn't even been fleshed out by the informed consent 22 workgroup yet. So we are not at the point where we're 23 bringing it to the committee for debate or discussion. 24 This is just FYI. 25 So just to reassure you that there will be, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 340 1 you know, ample opportunity, not only in -- you know, 2 within the setting of our meeting, but also in terms of 3 public comment because these things will be posted on 4 the web. So this is just -- it's been put on our 5 horizon and that is it. 6 PARTICIPANT: Okay. Thank you. 7 MS. BLEVINS: Brief comment. You wanted 8 facts, I just wanted to share a few quick facts. I 9 can't get into detail. 10 I'm going to share this with Abbey, the 11 consumer voice, and hopefully she can share this with 12 you. It's a gallup survey on how patients feel about 13 consent and involving research. And I would highly 14 recommend -- I know sometimes you think, well, we're 15 just hearing from those privacy advocates over there, 16 but we wanted to go out and find out how ordinary 17 citizens feel across the country and they really do 18 want consent before any further research is obtained. 19 And we're talking here about going through 20 medical records, doing the sociological research, not 21 just biomedical research. So I would highly urge you 22 to look at the will of the public in making these 23 decisions. 24 CHAIRPERSON MARSHALL: I can assure you, we 25 certainly will. And thank you very much. And, you PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 341 1 know, anything that you feel in the future needs to be 2 brought to our attention, don't wait for the meeting, 3 send it on. 4 Thank you. 5 Bob, do you need a last word? 6 DR. R. LEVINE: No. 7 CHAIRPERSON MARSHALL: Elliot, would you like 8 a last word? 9 DR. DORFF: Not if you put it that way. 10 CHAIRPERSON MARSHALL: Thank all of you. 11 That was some very interesting out-of-the-box ideas 12 here. I commend you on your work and thank all of you 13 all for staying overtime. We will see you tomorrow, I 14 hope. 15 [Whereupon, at 5:45 p.m., the proceedings 16 were adjourned, to be resumed at 8:30 a.m., on Tuesday, 17 April 30, 2002.] 18 - - - 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 Monday, April 29, 2002, was held as herein appears, and that this is the original verbatim transcript thereof, and is a full correct transcription of the proceedings. Cynthia D. Thomas Official Reporter PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443