1 UNITED STATES OF AMERICA DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + MEETING OF THE SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTIONS + + + + + Monday, July 31, 2006 + + + + + The meeting came to order in Salon C of the Grand Ballroom, The North Bethesda , MD at 8:00 a.m. Dr. Ernest Prentice, Chairman, Presiding. PRESENT: JOHN AGWUNOBI, MD, Assistnat Secretary for Health ERNEST D. PRENTICE, PH.D., Chair BERNARD A. SCHWETZ, DVM, PHD, Executive Secretary CATHERINE SLATINSHEK, MA, Executive Director KELLY BOOHER, Program Analyst JEFFREY BOTKIN, MD, MPH, Member CELIA B. FISHER, PHD, Member MYRON GENEL, MD, Member NANCY L. JONES, PHD, Member DANIEL K. NELSON, MS, CIP, Member NEIL R. POWE, MD, MPH, MBA, Member JAMES H. POWELL, MD. Member FRANCINE C. ROMERO, PHD, MPH. Member SAMUEL TILDEN, MD, JD, LLM, Member SUSAN L. WEINER, PHD, Member PATTY DECOT, Ex Officio Member AMY PATTERSON, MD, Ex Officio Member SANDRA SCHNEIDER, PHD, Ex Officio Member ROGER CORTESI, Alternate Ex Officio Member SALLY FLANZER, PHD, Alternate Ex Officio Member JOAN P. PORTER, DPA, MPH, Alternate Ex Officio Member LAURENCE UHTEG, MD, PHD, Alternate Ex Officio Member 2 ALSO PRESENT: MICHAEL CAROME, MD, OHRP DENISE GEOLOT, HRSA FELIX GYI, PHARM. D, MBA, CIP MICHAEL H. WOLF, Esq., OGC 3 I-N-D-E-X Welcome: Opening Remarks. . . . . . . . . . . . . .4 Introduction of New Members Remarks, John Agwunobi. . . . . . . . . . . . . . 10 Swearing in of New Members. . . . . . . . . . . . 18 Report of Issues, Bernard Schwetz . . . . . . . . 32 Federal Adverse Advents Task Force Update Amy Patterson . . . . . . . . . . . . . . . 46 Michael Carome. . . . . . . . . . . . . . . 59 Report of Subpart A Subcommittee Daniel Nelson . . . . . . . . . . . . . . . 93 Felix Gyi . . . . . . . . . . . . . . . . .114 Working Lunch/Ethics Training for . . . . . . . .187 New Members Michael Wolf Report of Subcommittee on Research. . . . . . . .221 Involving Children Celia Fisher Public Comment. . . . . . . . . . . . . . . . . .358 Discussion and Wrap-Up. . . . . . . . . . . . . .361 4 1 P-R-O-C-E-E-D-I-N-G-S 2 (8:00 a.m.) 3 DR. PRENTICE: Good morning, everybody. 4 Thank you for coming. You know, I left Nebraska 5 yesterday when it was 100 degrees and I hear our heat 6 wave is coming to Washington, so fortunately I'm 7 leaving on Wednesday when it's going to be 100 here, 8 but it's nice to be inside today. 9 This is the 10th meeting of SACHRP and 10 it's my pleasure to acknowledge Dr. John Agwunobi, who 11 is sitting right there, who is the assistant secretary 12 of health and human services. Thank you, Dr. 13 Agwunobi. We're delighted you could come. 14 I will remind you of our SACHRP Charter. 15 We will advice the secretary on all matters concerning 16 protection of human subjects with a particular 17 emphasis on vulnerable subject populations, and 18 certainly those of you who are familiar with our work, 19 you know we have concentrated on vulnerable subject 20 populations such as research involving children and 21 research involving prisoners. 22 The committee was formerly known as 5 1 NHRPAC, National Human Research Protection Advisory 2 Committee which was chartered by Donna Shelala. Our 3 Charter was initially issued in October 1st, 2002 and 4 then it was renewed on October 1, 2004. We are up for 5 renewal again and we are, of course, optimistic that 6 our Charter will once again be renewed. 7 As you know, we have rotating memberships 8 and I would like to take this opportunity to introduce 9 our new members, and in the interest of time I will 10 read very short bios. As a matter of fact, this comes 11 from the press release. The longer bios are in your 12 packets. 13 First, to my immediate left, between the 14 young lady right there, Celia, and Dr. Schwetz, we 15 have Dr. Jeffrey Botkin. He is currently a professor 16 of pediatrics and medical ethics and associate vice 17 president for research integrity of the University of 18 Utah. Dr. Botkin's a fellow of the Hastings Center 19 and chairperson of the American Academy of Pediatrics 20 Committee on bioethics. He has written extensively on 21 ethnical, legal and social implications of genetic 22 testing and research at the pediatric and adult 6 1 levels. Welcome, Dr. Botkin. 2 Next I have Mike Genel, is a professor 3 emeritus of pediatrics at Yale University School of 4 Medicine. He is a pediatrician with a subspecialty in 5 endocrinology. Dr. Genel served for ten years an 6 associate dean and director of the Yale University 7 School of Medicine, Office of Government and Committee 8 Affairs. His clinical interests are general 9 endocrinology, growth development and disorders of 10 sexual development. Welcome to the Committee, Dr. 11 Genel. 12 Next I have Dan Nelson to my immediate 13 left. I think Dan is familiar through all of this 14 because he is the co-chair of our subcommittee. He's 15 an associate professor of social medicine at 16 pediatric's and director of the Office of Human 17 Research Ethics, the University of North Carolina at 18 Chapel Hill. He has responsibility for providing 19 global oversight for 7 IRBs in approximately 400 20 research studies. 21 Next, Dr. Francine Romero at the end on my 22 right. Francine -- and I'm going to read you what she 7 1 used to do because she recently moved -- but she was 2 an epidemiologist and served as a director of the 3 Northern Plains Tribal Epidemiology Center at Rapid 4 City, South Dakota and the Center focused on 5 collecting the reported health data regarding the 42 6 specific northwest tribes. She has both a personal 7 and a profession interest in native American and 8 Alaska-native health issues and she is a member of the 9 Pueblo of UMS New Mexico where she is now the director 10 of the Health and Human Services. 11 Samuel Tilden is right there. Samuel 12 Tilden is a professional of pediatrics and deputy 13 provos for human subjects research and a research 14 compliance officer. He is also a JD. We used to have 15 a JD on our initial committee, Dr. Mark Barnes, so 16 we're delighted to have another lawyer amongst us, and 17 Dr. Tilden is at the University of Alabama at 18 Birmingham. 19 He is a pediatrician with sub-specialties 20 in pediatric pulmonology and critical care and has 21 served on numerous national and international advisor 22 panels and committees. He is an experienced clinical 8 1 investigator of the conduct of clinical trials in 2 children and licensed to practice law. Welcome to the 3 Committee, both of you. 4 This is the current list of the members of 5 SACHRP is a partnership with OHRP. We work together. 6 As you know, OHRP provides liaison staff to SACHRP. 7 They're intricately involved in everything that we do, 8 so thank you very much. 9 I'd also like to recognize Cathy 10 Slatinshek and Kelly Booher. They're the individuals 11 who organize everything I do. I do nothing; I just 12 show up 15 minutes before hand and the slides are all 13 ready for me and all I have to do is talk. 14 I also want to acknowledge the 15 participation of our ex officio members of SACHRP. 16 They are at many of our meetings, including our 17 subcommittee meeting, so thanks to all of the ex 18 officio members. 19 Now we're going to delay Dr. Schwetz's 20 report on the issues until after we have, ahead, Dr. 21 John Agwunobi and also swear in the new members. But 22 before we do that, I would like to tell you a little 9 1 bit about Admiral Agwunobi and I will read a short 2 version of his bio. 3 Dr. Agwunobi serves as the Secretary's 4 primary advisor on matters involving the nation's 5 public health. He also oversees the U.S. Public 6 Health Service and its commissions corps for the 7 Secretary. He is a seasoned public health 8 professional with experience in healthcare delivery, 9 managed care and health policies. 10 Prior to becoming the ASH, Dr. Agwunobi 11 served as Florida's secretary of health and state 12 health officer under Governor Jeb Bush from October 13 2001 to September 2005 and during his tenure he 14 confronted many public health challenges. As a 15 pediatrician Dr. Agwunobi has dedicated himself to 16 working with under-served populations. 17 Before moving to Florida he was Medical 18 Director and Vice President of Medical Affairs and 19 Patient Services at the Hospital for Sick Children 20 which is in Washington, D.C. 21 In addition to his medical degree, Dr. 22 Agwunobi holds a master's of business administration 10 1 from Georgetown University and a master's of public 2 health from Johns Hopkins. He's the recipient of 3 numerous honors and awards, including the public 4 administrator of the year and I might add that our 5 newest members are also the recipient of numerous 6 awards as well, which I did not read. 7 Dr. Agwunobi sees his role as the 8 Assistant Secretary for Health as an opportunity to 9 enhance the Secretary's efforts to further the mission 10 of HHS and the health of the nation by building, 11 strengthening and leveraging relationships across the 12 public health community and the U.S. Pubic Health 13 Service. 14 Dr. Agwunobi, once again, welcome. Would 15 you step up here, sir, please? Would you like to 16 level your mic? May I sit, Mr. Chairman? 17 DR. PRENTICE: Absolutely. 18 DR. AGWONOBI: Thank you, Mr. Chairman, 19 for that wonderful introduction and for introducing to 20 the world the reality that pediatricians are taking 21 over. And was I the only one that noticed that all 22 the new members are pediatricians, as am I? I applaud 11 1 whoever makes these decision and choices to be. This 2 is great. 3 Good morning, everyone. I am the 4 Assistant Secretary for Health and within that title 5 I do serve as the principle advisor to the Secretary. 6 Later this afternoon or tomorrow, when I'm given the 7 opportunity, I will advise him that SACHRP is hard at 8 work, refreshed with new members and I think doing 9 critical, critical work in protecting human research 10 subjects. 11 I thank you for your willingness to serve 12 on the Secretary's Advisory Committee on Human 13 Research Protections and this is my second visit. 14 Each time is a pleasure. I know that you've made 15 great progress over the years. Did I hear you say 16 this is the 10th meeting of this committee? 17 DR. PRENTICE: Tenth meeting, yes. 18 DR. AGWONOBI: I have to recognize -- Bern 19 just informed me that there are very few individuals 20 that have been on the Committee longer than two 21 meetings. Only one or two have been here for more 22 than two or three meetings, so we're all relatively 12 1 new. However, clearly, as described by the Chairman, 2 everyone is highly qualified to be on this Committee 3 and to take on the work that you face. 4 I am gratified and comforted to see the 5 diversity of the membership in terms of its 6 professional background and position of advocacy. 7 It's pretty clear that we cover almost the entire 8 waterfront. 9 I know that we have five new SACHRP 10 members so I'd like to talk a little bit about 11 SACHRP's Charter, if I may, Mr. Chairman. 12 As most of you are aware, SACHRP is tasked 13 to advise the Secretary on matters pertaining to the 14 protection of human subjects and research. A lot of 15 that is codified in law but like ethical issues and 16 issues that relate to research, much of it unfolds in 17 time and involves interpretation. Your thoughts are 18 critical to the future as we expand the horizons of 19 research. 20 Anyone who's been listening and watching 21 TV will realize these are wonderful times in science. 22 Science aggressively tears down barriers, increasingly 13 1 it appears to me, at an accelerated rate. Your work 2 has never been more relevant than it is today. 3 The Charter states specifically that 4 SACHRP will have special emphasis on a number of 5 issues including those that are currently being 6 considered by your subcommittees. These include the 7 conduct of research involving special populations, 8 such as neonates and children under subpart D, the 9 current requirements for research involving prisoners 10 as subject, in subpart C, and the issues involving the 11 concept of accreditation of research protection 12 programs. 13 Currently the Committee is working to 14 clarify policies affected by the subpart A portion of 15 the regulation and I look forward to an update on 16 their interpretations -- thank you for your work -- of 17 issues such as expedited and continuing review, and 18 proposed guidance on minimal risk. 19 Also, your subcommittee on research 20 involving children will be presenting its report, I 21 believe, at this meeting if I'm not mistaken, and 22 conclusions. And I look forward to reading that 14 1 report and reviewing those conclusions. 2 I know that this Committee has produced 3 recommendations to the Secretary of HHS and that the 4 Secretary has asked OHRP and Bern and his fine team to 5 keep us apprised -- the department, himself and others 6 -- of progress on these proposals. 7 I do want to just let the members know 8 that your work is followed very closely by each of the 9 operational division in HHS, CDC, NIH, FDA, CMS, HRQ, 10 SAMSA. Bern would testify to this: They are very 11 interested in the work that you do because it affects 12 not only the grants and federal dollars that go out 13 into the world and to the protections that surround 14 those research grants, it also affects directly the 15 work of those agencies. 16 I know that many of our ex officio members 17 from other departments also take your work back across 18 the federal government into other departments -- 19 Department of Defense, Department of Education and 20 many others. I think it's important that you realize 21 the influence not just the research community, but you 22 also influence government with your work. 15 1 The issues that you deal with are all 2 highly important. I know they're diverse and they're 3 numerous, but you are selected because you are clearly 4 qualified and you excel in your fields and in your 5 backgrounds and in your professions, and you've been 6 selected because it's thought that you represent and 7 have a good understanding of the issues that we'll 8 deal with. 9 Your recommendations are also very 10 important to the subjects of research and that's -- 11 let me try and boil this down -- it's about real human 12 beings. This is not some bureaucratic, red-tape-like 13 process. This isn't just another meeting. The work 14 that you do, no doubt at some point in its journey 15 over time saves lives, protects dignity, furthers 16 research. I'm personally am firmly of the belief that 17 all research needs to be conducted with in the 18 parameters of the kind of work that you do. 19 The Institute of Medicine has released its 20 report on ethics of conducting research involving 21 prisoners and I'm told that SACHRP will be receiving 22 a briefing on that report tomorrow. You know what I 16 1 know, which is that no human being is less valuable 2 than another, and it's critical the research in those 3 populations be given extra special attention. 4 I'll be anxious to hear your thoughts on 5 the report and the next steps that the Committee might 6 take to move ahead, protections in those issues. 7 Another important topic that you will 8 discuss tomorrow is the issue of protections of the 9 decisionally-impaired subjects of research. I'm a 10 pediatrician who worked with the disabled and the 11 decisionally-impaired over the years in different 12 settings and I recognize this is critical work. 13 I know that you'll be asked to decide 14 whether or not guidance or additional regulations are 15 needed for this subject population, and I assure you 16 your recommendations will be taken very seriously. 17 Because of your expertise in many of these 18 areas I, along with Bernie, Bernard Schwetz, Dr. 19 Schwetz of OHRP look forward to continuing to work 20 both together as we receive your recommendations, but 21 hopefully along with you over time as we deliberate 22 and discuss on all of these important issues. 17 1 I recognize that there aren't a lot that 2 will come up to you in the street or in your workplace 3 and thank you for your work on this Committee because 4 it is largely invisible to the average person. Other 5 than those that have been kind enough to grace us with 6 their presence in the audience, most don't realize 7 that the protections that are built around -- to 8 protect human research subjects don't just come out of 9 law or come out of the sky; they come out of 10 thoughtful and prolonged and sometimes agonizing 11 deliberation. 12 Very few researchers realize how much work 13 goes into assuring the infrastructure of protection 14 for human subjects that you embody as a governing 15 board, so to speak. You have quite a charge, quite a 16 charge, a solemn charge. 17 Mr. Chairman, speaking of solemn charges, 18 there is a procedure that every new member has to go 19 through. I believe it's more than just red tape. I 20 believe it is a solemn ceremony that symbolizes the 21 importance of the work that's done on this Committee 22 and it's the swearing in of new members. 18 1 I want to swear in, before I take 2 questions from your Committee, if I might swear in the 3 new members. 4 DR. PRENTICE: Yes, you may. Would the 5 new members please step forward? 6 DR. AGWONOBI: This way I'm forced to tell 7 the truth when they ask a question. Raise your right 8 hands. 9 (Whereupon, new members were sworn in.) 10 DR. AGWONOBI: Thank you very much. We 11 have one other very important task before we enter 12 into the conversation. 13 DR. PRENTICE: We have one of our members 14 who is departing, unfortunately. I would love to have 15 all of you stay on more or less permanently, but 16 that's really not reality and we understand you have 17 other things to do, so it's my pleasure to ask Susan 18 Weiner to please come up. This is the certificate. 19 DR. AGWONOBI: If I may, I'm just going to 20 read a closing paragraph from a letter to Susan from 21 Secretary Michael Leavitt letter that I have here. 22 It's a long letter; it goes on and on and on, but a 19 1 quick sentence: "I truly appreciate the level of 2 dedication and loyalty that you have demonstrated in 3 assisting the department's efforts to address the many 4 matters that impact this important area of public 5 health and science. Although it has become necessary 6 to end your appointment to the Committee it is hoped 7 that we may be able to call upon you for further 8 assistance and advice over time. You have provided a 9 valuable service to the department during your tenure 10 as a member of Committee. Sincerely, Michael O. 11 Leavitt." 12 (Applause.) 13 DR. AGWONOBI: In appreciation for the 14 service you've provided as a member of Secretary's 15 Advisory Committee on Human Research Protections from 16 January 2003 to July 2006, the U.S. Department of 17 Health and Human Services, as headed by Secretary 18 Michael O. Leavitt, presents you, Susan L. Weiner, 19 with this. 20 (Applause.) 21 DR. AGWONOBI: So, Mr. Chairman, what is 22 your pleasure? 20 1 DR. PRENTICE: If you have time, I would 2 be delighted if you could entertain any questions that 3 members of SACHRP might have for you. 4 DR. AGWONOBI: I should probably ask for 5 everyone's forgiveness. After this quick conversation 6 I'm going to have to run, so you might also use this 7 as an opportunity to task me until our next visit. 8 DR. PRENTICE: Oh, come on. 9 DR. AGWONOBI: How about in the audience? 10 Are there any questions, concerns, comments for me or 11 for the membership prior to beginning their work? 12 DR. PRENTICE: How's the bird flu 13 preparation coming? 14 DR. AGWONOBI: Bird flu preparation is 15 actually coming along pretty well. As you know, the 16 federal government is engaged in about three or four, 17 perhaps five major pieces. Firstly, investing in the 18 science and in advancing the industry associated with 19 vaccines. No doubt, along the way, in the pursuit of 20 that particular goal, whether it be the stockpiling or 21 the administration of -- the preparation of 22 stockpiling or administration of vaccine, I have no 21 1 doubt there will be research involved along the way. 2 The whole notion of the administration of research 3 vaccines, IND-type vaccines, in the presence of a 4 pressing global emergency offer interesting challenges 5 and opportunities for discussion. 6 In addition to that, we pursue through our 7 investment in science and research, new antivirals as 8 we face the challenge of the next pandemic, an 9 inevitable challenge, whether it be the next five 10 years or the next twenty, at some point there will be 11 another pandemic. As we pursue efforts to prepare we 12 begin to realize that there's a need to find, 13 manufacture and stockpile new antivirals. Our 14 reliance on Tamaflu and Rulenza clearly isn't enough. 15 We also continue to work on issues like 16 surveillance, global and domestic, working with 17 international partners to further their capacity to 18 respond. There's perhaps a higher-level discussion 19 about obligations to other nations and poor nations as 20 they prepare and what our role should be in those 21 settings. 22 We also continue to work to help states 22 1 and local communities prepare for and be ready to 2 stand as individual communities in the face of a 3 pandemic given that it will affect every community 4 simultaneously. It is just a necessity, a fact, that 5 every community has to have a certain amount of 6 preparedness for us to be able to respond as a nation. 7 On top of all of that, we continue to find 8 ways to improve our lab diagnostic capabilities and 9 clearly a part of the requires that we test and 10 manufacture new diagnostics in order to provide for 11 rapid identification and the rapid management of 12 individuals with, potentially with, PanFlu, pandemic 13 influenza, in the future. There's a lot of work going 14 on, Mr. Chairman. 15 DR. PRENTICE: Thank you. Perhaps -- 16 DR. AGWONOBI: If you could just very 17 quickly run to the microphone and if you could state 18 your name or the organization, whether you represent 19 one, or yourself. Whichever. 20 MR. GERELL: I'm a clinical research 21 consultant. My name's Jay Gerell and am a graduate of 22 UNC School of Public Health. At any rate, I was just 23 1 hoping to make one comment about HHS perhaps working 2 with Congress in furthering antibiotic development, 3 because of course, with staff and other things, just 4 as you were mentioned bird flu, the other have been 5 coming epidemic is simply the lack of antibiotics. 6 DR. AGWONOBI: You're absolutely right. 7 You know, since penicillin, decades ago, we're very 8 proud of the fact that we've developed so many so 9 quickly -- antibiotics and antibiotic classes. 10 But clearly we've also along the way begun 11 to recognize that nature is keeping up with us in 12 terms of resistance and in terms of emerging diseases 13 and therefore the obligation for science to continue 14 that pursuit is important. 15 I can assure you that not only are we 16 pursuing aggressively investments in science that 17 relate to antibiotics but we're also pursuing 18 investments in clinical science that relate to slowing 19 down the march of resistance to antibiotics over time. 20 Clearly much of the work that you do will relate to 21 not only antivirals, in terms of the present pandemic, 22 HIV, AIDS, future pandemics, H5N1 or other influenzas, 24 1 and the bacteriological and mycological world in terms 2 of antibiotics and chemo-therapeutics. 3 DR. FISHER: I was just wondering in terms 4 of the avian flu vaccine and some of the research 5 going on, whether or not HHS anticipates children 6 being involved in any of this research and what 7 thoughts you have on how that might go forward, given 8 there's a risk of not doing research with children as 9 well as doing research? 10 DR. AGWONOBI: I believe that not just in 11 terms of vaccine, but also antivirals, that there is 12 in some of the cases -- I'll put it this way: There 13 is a recognition that in protecting our nation we have 14 to also protect our children. 15 In fact, there's a growing recognition 16 that perhaps children are a central piece of a 17 pandemic in that it would appear through modeling and 18 perhaps through limited research, that one of the main 19 ways that influenza and seasonal influenza and indeed 20 during pandemics, that children and congregations of 21 children, schools and daycares, etc., may be one of 22 the main ways that influenza viruses spread through a 25 1 community. 2 We've come to realize, therefore, that our 3 strategies have to involve, whether they be using 4 countermeasures, antivirals or vaccine, or simply in 5 our public health interventions -- social distancing, 6 and others -- that we have to focus on children. 7 I know for a fact that research is gearing 8 up both within industry and within science research, 9 non-industrial science, to try and broaden the data 10 and the information that we have as it relates to 11 children. I can't tell you the specifics because I 12 don't know what the specifics are, but specific 13 protocols that are being proposed or that are 14 underway. 15 But it is important that we recognize that 16 there are two main areas with antivirals that might 17 involve children: The first is in the development of 18 a pandemic influenza vaccine, a vaccine that would be 19 used to respond to a pandemic, clearly our goals would 20 be to try and involve -- our goal is to have 300 21 million courses of such an antibiotic within 6 months 22 and a vaccine within 6 months of a pandemic rearing 26 1 its ugly head. 2 It's therefore clear, 300 million, that 3 every citizen -- our goal would be to try and 4 vaccinate every citizen, children included. There is 5 a discussion underway, and I would urge SACHRP at some 6 point to at least deliberate on these issues, if only 7 over lunch if not formally, on issues related to 8 prioritization -- who should go first. 9 Now, if such a vaccine were a research, an 10 IND non-licensed vaccine, than very clearly there are 11 other very relevant discussions that are involved in 12 that. Does the prioritization change if its licensed 13 or if it's not, and those kinds of things. Are there 14 special populations that need to be treated 15 differently in such a circumstance? 16 The second big area is what we call a pre- 17 pandemic vaccine. Today, for example, we are 18 stockpiling vaccine for H5N1. We have the vaccine and 19 are stockpiling it. But we recognize that H5N1 may or 20 may not be the source of the next pandemic and so, you 21 know, there are questions that arise, well, how should 22 you use this current vaccine? Should you use it to 27 1 vaccinate responding communities, first responders, 2 vaccine manufacturers, hospital staff, those kinds of 3 individuals, with the possibility that in doing so 4 you'll have a protected population if H5N1 becomes a 5 pandemic? Should you hold off and wait for some 6 future change in the virus before administering a pre- 7 pandemic vaccine? 8 These are all questions that are perhaps 9 beyond the charter of this group, but given that a lot 10 of this involves research, I would imagine that your 11 thoughts and your notions on these things would be 12 relevant, germane and important. I'll take one more 13 and then I have to run. 14 DR. JONES: It's a little bit of a change 15 of a topic. The Institute of Medicine, the prisoner 16 report actually have several themes that have broader 17 scope for human research protection. In one they 18 recognize that there's a gap in oversight, you know, 19 things that are funded by HHS, have OHRP's oversight, 20 but there are many other things that are done in 21 research that sort of fall in between the cracks. 22 Another recommendation that they seem to 28 1 make are a push for more and more resourcing for 2 oversight or even a new -- in this particular report 3 they're asking for a new kind of person that would be 4 a liaison oversight of research in prisoners. But it 5 seems like that all of this ends up making research 6 more expensive and these mandates for doing human 7 research protection are very, very important but the 8 resourcing isn't always available or maybe HHS has 9 some ideas about how actually more resourcing can go 10 for this important job of protecting human research 11 subjects. 12 DR. AGWONOBI: I haven't seen the report 13 yet and I do look forward to seeing it, but more 14 importantly, reviewing your thoughts on its contents 15 as a formal group. I know that there's an 16 arrangement. Bernie's kind of setting up to have me 17 briefed on not just the report, but on what you guys 18 think about it. 19 I just want to correct one thing that you 20 said. The OHRP does have responsibility beyond the 21 walls of HHS in terms of oversight of human research 22 protections and I'm pretty certain that the law that 29 1 provides OHRP with its authorities, the regulations 2 that are built to describe for OHRP its purview, that 3 they're very clear that they extend into anywhere that 4 research is conducted, at least as it relates to the 5 use of federal dollars -- and I'll let Bernie correct 6 me if I'm way wrong here -- but I'm pretty certain 7 that there are opportunities to improve the way we do 8 things, both with prisoner populations and beyond. 9 I mean, the truth of the matter is we 10 wouldn't need this Committee if we were getting it 11 right across the expanse of research. There are 12 opportunities to improve and your guidance, therefore, 13 is absolutely critical. Money. Money. More 14 expensive. 15 Our nation has recently gone through a 16 series of debates that relate to -- I know I'm perhaps 17 treading on some sensitive ground here -- on stem cell 18 research and it was primarily a discussion of funding. 19 I watched it and I indeed participated in it and I'm 20 not going to tell you my personal position on this. 21 I'm just going to state this, that it was pretty clear 22 to me that a subcurrent through the entire discussion 30 1 was the notion of the parameters in which research are 2 conducted, what they should be. 3 Whether we're talking about the ethical 4 parameters or the research, human research, subject 5 protection parameters -- and they overlap to a great 6 degree in many areas -- I think it's important that we 7 recognize that it's not an expense. Whatever it is 8 that we as a nation decide, those parameters should be 9 around whatever area of research, whether it be 10 controversial stem cell, or less controversial 11 clinical trials in adults, I believe strongly that we 12 should never look at those parameters. 13 When we decide on what they should be as 14 a society we should never look at them as being an 15 additional expense. They are the foundation. It's 16 not extra; it's the cost of doing research in our 17 value system. 18 It's pretty clear to me that the federal 19 government should do what it can. NIH is a wonderful 20 organization that has doubled in size over just the 21 last five years in terms of its budget. A commitment 22 to investing in research. I recognize that we also 31 1 need to have a commitment in those parameters, an 2 investment in the protections that we hold, whether 3 they be (Microphone off briefly) 4 I think it's important that whatever we 5 do, that we invest in it and to show our commitment to 6 it. There's always going to be a little bit of 7 tension about how much goes into the protection and 8 how much goes into the research itself, and this 9 balance is I think what you were alluding to. That as 10 research expands we need to at least make sure that 11 our research protections, and Bernie's shop, and your 12 work keeps up with that research. 13 I'll do what I can to support it. Bernie 14 and I are going to have to have a long conversation, 15 and I would urge you to participate in the long-term 16 challenges. In other words, let's try to skate to 17 where the puck is going to be. 18 It is hard in the federal government to 19 meet funding challenges realtime. You have to predict 20 what those funding challenges are going to be way out 21 into the future and then gear up a strategy to assure 22 that you have those funds. 32 1 If you're fighting for funds for this 2 year, you're too late, so we do need to try and figure 3 out what are we going to need ten years from now and 4 make sure that we have a strategy to get there. And 5 Bernie, a special challenge to you. You and I are 6 going to have to talk about this. All right. Mr. 7 Chairman, may I? 8 DR. PRENTICE: Yes, you may. 9 DR. AGWONOBI: Thank you very much. 10 (Applause) 11 DR. PRENTICE: As Dr. Agwunobi is leaving, 12 I would really like to publicly thank him for coming 13 to visit us and he knows he's always welcome. You 14 know when our next meetings are, sir. I hope that you 15 will find it in your schedule to be able to attend, so 16 we really appreciate your support, your remarks and 17 your response to our questions. Thank you. Bern? 18 Would you like to report on the issues, please? 19 DR. SCHWETZ: Sure. If I many comment on 20 Dr. Agwunobi first, and not just because he's gone. 21 (Laughter) 22 DR. SCHWETZ: It's very reassuring to me 33 1 and to the rest of us in OHRP to have him in the 2 position that he is, because he is supportive of not 3 only what we do, but what our mission is -- what we 4 represent. For him to come to our meetings is 5 impressive. For him to understand the issues is 6 impressive, because you've got a sense of just part of 7 what his plight is all of, and it's all of a long list 8 of things that are crisis of the day, crisis of the 9 week. So for him to take the time to share with us 10 and to reassure us that he's aware of what we're doing 11 and thinks it's important is a very positive thing for 12 all of us. 13 Let me comment on a few things that are 14 going on, have gone on: These first two have already 15 been mentioned but you, as SACHRP, have made 16 recommendations that we would make some progress on 17 adverse-event reporting, and you're going to hear more 18 about that this morning, and I think we are making 19 progress. 20 The fact that we have the IOM report in 21 hand regarding the ethics of doing research involving 22 prisoners, I'm glad that we have that now and it will 34 1 allow us to make some decisions and to take some 2 advise from you on where we should be going regarding 3 that. 4 Let me comment on the plans that we have 5 in place for the National IRB Conference coming up in 6 November 20th and 21st here in the Washington area. 7 The objective of this is for the community to review 8 the alternatives to local IRBs and the issues that are 9 behind that. How do we use alternatives to the local 10 IRBs? Under what circumstances? What other 11 considerations? And why don't people use alternatives 12 to local IRBs? 13 And we had a workshop last fall that I 14 think was very successful in helping to identify what 15 some of those issues are about looking at an 16 alternative and we use the information from the 17 workshop to help design this national conference 18 that's going to be held now at the Marriott Warman 19 Park Hotel on November 20th and 21st here in the 20 Washington area. 21 We will continue to focus in this day-and- 22 a-half meeting on issues like liability concerns, the 35 1 quality of the review relative to various models of 2 IRB review, the cost, the timing, local context, other 3 issues of that kind that are all on the minds of 4 people who make the decision that, yes, I would 5 consider an alternative to my local IRB or I would 6 not. 7 So the conference in November will be to 8 bring people together and have further discussion 9 about whether these issues that are cited as the 10 reasons why we don't consider alternatives to local 11 IRBs are in fact real or are they excuses. And as a 12 result, the people that we are wanting to get together 13 at this conference include institutional attorneys who 14 are, I think, particularly responsible for this kind 15 of decision that would be made, whether you would use 16 a local -- your own local, or an alternative to it. 17 Institutional officials also have a 18 significant impact on how these decisions are made. 19 Investigators have input, IRB members have input, so 20 we are gathering a fairly broad range of people and 21 others beyond whom I mentioned, but the purpose is to 22 get these people to talk more about these issues and 36 1 find out how can we get beyond the hurtles that are 2 cited as the reason for not considering alternatives 3 to local IRBs. 4 At a time when it's recognized, 5 particularly in the multi-site studies, all the 6 redundancy that has to occur in multi-site studies 7 represents part of the burden that we're concerned 8 about in having enough attention to pay to the issues 9 that we really should be paying attention to. 10 So it's a conference that we are working 11 on now to continue to flush out the details, but it's 12 one that I am looking forward to with the hopes that 13 it will also have some impact. 14 A couple of other issues: Within July, 15 this past month, we published in the Federal Register 16 a notice that we hoped would clarify that the 17 requirements of 45CFR46 or HHS conducted or supported 18 research apply not only domestically but 19 internationally as well. There's been confusion in 20 the field by virtue of the FWOA document that when 21 there is a list of other regulatory procedures that 22 are cited there, the assumption has been that if I 37 1 check DIOMS than I don't have to comply with 45CFR46 2 or the Declaration of Helsinki or some other document. 3 That hasn't been the feeling of OHRP, and we thought 4 it was critical that we clarify that. If you were 5 receiving HHS funds to do research at a non-U.S. site, 6 you are still committed to 45CFR46. So it isn't that 7 you have a choice of one or the other; you may choose 8 to work in compliance with what is in CIOMS, but it 9 doesn't mean that you have the option of not following 10 45CFR46. 11 This gets into the discussion of 12 equivalent protections and the Secretary has the 13 responsibility to determine that if somebody is going 14 to follow some other set of guidelines that in fact it 15 produces equivalent protections. But the reality is, 16 none of those have been evaluated in that context to 17 determine that there is equivalent protection. 18 And it doesn't mean that there won't be 19 one in the future, but as of now, 45CFR46 stands alone 20 in that regard. The Federal Register notice also 21 pointed out that a decision has to be made by the 22 other signers of the common rule on how they want to 38 1 handle that. This is the way HHS is going to handle 2 it, but the other departments have to decide that on 3 their own. 4 A comment on the long-standing question 5 of: What is research? We have been working with OHRP 6 to develop some guidance that helps to address this 7 question of what is research and what isn't research 8 in this large community, and we have a draft that the 9 ASH has asked -- the Assistant Secretary for Health -- 10 has asked us to now put together a council within HHS 11 of representatives from all of the agencies to review 12 our new guidance on the definition of research, and 13 that's something we're going to be working with. 14 We don't know exactly how many meetings 15 this is going to take, but we now have most of the 16 names of the other agencies who are going to work on 17 this to review our document, come up with 18 recommendations, suggestions, then we'll go back to 19 the ASH with our revised document and have discussion 20 of where we go next. 21 And one of the other things that we have 22 done with other guidance is give it to the other 39 1 agencies under the common rule for them to review and 2 have input. The council, I said, was within HHS, so 3 one possibility is that we would go beyond that and 4 then go public for public comment on this. 5 So we know this is a difficult task that 6 others have talked about and some have said, you know, 7 don't bother; you'll never get there from here. But 8 the issue is too important to leave alone, so we're 9 making an effort to try to clarify this, so that's 10 something that we'll continue to work on for some time 11 I'm sure. 12 A couple other real quick things. To 13 reinforce that we continue to have an effort and a 14 desire within OHRP to reach out to the public and to 15 minority groups and ethnic groups to help them 16 understand what they should know better about being a 17 subject of research. So we have produced a document, 18 more of a generic document, that the message is: 19 Research is important and you have a choice; it's your 20 choice as a member of the public whether or not you 21 want to participate in research, but here are some 22 things you ought to know about it and here are some 40 1 people whom you can call if you want help, if you have 2 questions. 3 So we're trying to reach out to the public 4 to encourage the public to understand what it means in 5 terms of opportunity as well as risks, to be involved 6 in research. While we are very close to having two 7 additional versions of the tri-fold document -- one 8 that's in Spanish and the other one in Vietnamese -- 9 so we continue now to work on getting this out to a 10 broader part of the population, and to make sure that 11 we're doing this in a way that people can understand, 12 and that it's culturally sensitive, so our outreach 13 effort continues. 14 The last thing is that you are aware that 15 we had an effort last year to interview the people 16 who were involved in the writing of the Belmont Report 17 and in fact I'm pleased to say now that on our website 18 there are links to 19 of the interviews that we did to 19 the people who played the key role in getting the 20 Belmont Report out. 21 And so if you want to get onto our 22 website, you can directly see those interviews. We 41 1 have four more people to interview yet, and I'm hoping 2 that that will be completed in this year but it was 3 interesting for me to be involved in those interviews, 4 certainly, and I think there is information that 5 people would benefit from going back and listening to 6 some of the comments that these people made who were 7 responsible to a large extent of the basis for the 8 discussions and the arguments that we have today. 9 Ernie, with that, I'll quit. 10 DR. PRENTICE: Thank you, Bern. Any 11 questions? Celia? 12 DR. FISHER: I may have had a senior 13 moment over the years but has the risk recommendations 14 from subpart D in terms of defining minimal risk -- 15 those have been approved, and has the permission, the 16 ones for 408 been approved by HHS? 17 DR. PRENTICE: The Secretary Leavitt 18 accepted the last set of recommendations which 19 included definition of minimal risk, minor increase 20 over minimal risk, disorder, financial ability, etc. 21 We're waiting for the completion of the Children's 22 Subcommittee's work in terms of awards and then we'll 42 1 put together the final set of recommendations. I have 2 a copy of the letter if you'd like to review it before 3 you visitation, okay? All right. Yes? 4 DR. GENEL: Bern, has there been any 5 thought about further dissemination of those vignettes 6 from the writers of the Belmont Report publication, 7 either free-standing or in one of the ethics journals 8 because I think that sort of historical record I think 9 is very important, and it would be very useful to have 10 this outside of just the website. 11 DR. SCHWETZ: Thanks, Myron. We'll 12 certainly consider that. I think the first 13 opportunity was to get this on tape while these people 14 are still available to us because there are a lot of 15 people in the field today who have never met these 16 individuals, have never seen them, so put a face to a 17 name was a high priority. 18 Your suggestion is an interesting one and 19 I, myself, and maybe some of the other Committee 20 members have who have been developing this have 21 thought about putting that into a textural form. 22 We'll give that some more thought. Thanks, Myron. 43 1 DR. PRENTICE: Okay. All right. As we 2 customarily do, this is the overview of the charges to 3 our two subcommittees. First the subcommittee on 4 research involving children under the co-chairship of 5 Celia Fisher and Susan Kornetsky. Susan, 6 unfortunately can't be here, but Celia is. 7 They've been working very, very hard ever 8 since the inception of SACHRP and they have produced 9 a whole series of recommendations pertaining to how we 10 should effectively interpret additional protections 11 for children. Celia will present the report of the 12 latest work of the subcommittee at this meeting. 13 And then our newest subcommittee, of 14 course, the subpart A subcommittee and are looking at 15 all aspects of the basic protection for human subject, 16 subpart A, and they will also present some of their 17 work to date for consideration by SACHRP and the co- 18 chairs are Felix Gyi and Dan Nelson. 19 And while I think about it, I would like 20 to publicly thank all of the members of the 21 subcommittees that are not listed on these slides but 22 certainly you know how hard everybody works, and it's 44 1 a collective effort to produce the recommendations 2 that finally come to SACHRP. 3 Now I would entertain an motion for 4 approval of the minutes from the last meeting which 5 I'm sure you spent a great deal of time reading. 6 MR. NELSON: Ernie, can I just ask for a 7 point of order? 8 DR. PRENTICE: Yes, you may. 9 MR. NELSON: If we actually did review 10 them and found just an error in fact that should be 11 corrected that shouldn't need a lot of discussion, can 12 we just pass that? 13 DR. PRENTICE: Yes, you can just pass that 14 on if that would be acceptable to everybody. I'm 15 still waiting for a motion, however. 16 DR. POWELL: So moved. 17 DR. PRENTICE: A second? 18 DR. POWE: Second. 19 DR. PRENTICE: Thank you very much. Any 20 further discussion? All those in favor? Any opposed? 21 Any abstentions? 22 (Unanimous approval.) 45 1 DR. PRENTICE: Motion carries. Overview 2 of the meeting agenda for today. We've already 3 accomplished part of our agenda, so I won't go over 4 that, but in about another two minutes we will have an 5 update of the work of the Federal Advisory Event task 6 force by Dr. Amy Patterson and Dr. Mike Carome. We'll 7 have a short break. Then we'll the report of the 8 subpart A subcommittee. 9 At lunchtime it will be a working lunch 10 for SACHRP members because the new members have to go 11 through what's called ethics training and there will 12 be an individual, a Michael Wolf, who will provide 13 that training. 14 At 1:00 we will reconvene for a report of 15 the subcommittee on Research Involving Children and 16 Celia will present that. We'll have a short break. 17 We will continue, then, at 2:45 and knowing you, 18 Celia, you'll have no problems continuing. And then 19 at 4:00 to 4:30 we'll have public comment and then at 20 4:30 to roughly 5:00 it'll be discussion and wrap-up, 21 so it's a busy agenda as usual. 22 So with no further adieu, I assume -- is 46 1 Amy going first? Okay. Let's get started. I'm going 2 to very briefly introduce Amy Patterson who doesn't 3 really need any introduction, in the interest of time. 4 I think everybody knows that Amy is the 5 Director of the Office of Biotechnology Activities, 6 otherwise known as, by the acronym OBA, and she has 7 been really, right from the beginning of our first 8 meetings of SACHRP, been intimately involved in many 9 of our activities and in particular as far as SACHRP 10 is concerned, Amy has been involved in trying to seek 11 a resolution to the Adverse Event problem and she's 12 going to be talking about the activities of her 13 committee, the Federal Advisory Task Force on Adverse 14 Events, so Amy, thank you for agreeing to talk with 15 us. 16 DR. PATTERSON: Thank you, Mr. Chairman 17 and members of the Committee and members of the 18 audience. It's a great pleasure to be here today and 19 on behalf of my sibling agencies, present to you an 20 update on a coordinated federal policy initiative 21 that's aimed at harmonizing and optimizing adverse 22 event reporting in clinical research. 47 1 This slide shows you but a handful of the 2 many forms for reporting adverse events to the federal 3 government and these forms are emblematic of some of 4 the underlying issues in terms of the divergence among 5 the various federal reporting policies currently in 6 place. 7 These policies differ not only in terms of 8 the threshold for reporting, the scope or content of 9 what's reported, but also the time frames for 10 reporting. And we have a some good evidence to 11 believe that this divergence creates not only 12 confusion. It can, on occasion, actually lead to non- 13 compliance, inadvertent non-compliance, even among 14 well-intentioned investigators or institutions. 15 And then also we have heard increased 16 costs, training costs, in terms of teaching clinical 17 coordinators, investigators and others how to comply 18 with the various policies. 19 But I think one of the greatest costs that 20 this divergence creates is the cost to human subjects 21 protections. Because of the lack of standards, 22 because of often incomplete reports and resulting poor 48 1 quality of information that are held for analysis, we 2 lose valuable information that could lead to insights 3 on how to better design future studies and alter the 4 informed consent, or stopping rules or monitoring 5 plans for studies currently underway. 6 This Committee recognized the importance 7 of these issues and requested that a task force be 8 assembled whose charge was superposed of mechanisms, 9 methods and approach to streamlining, harmonizing and 10 optimizing how the federal government collects adverse 11 event information, what we do with it when we get it - 12 - how do we analysis it, and how do we communicate 13 about those events back to the research community and 14 to patients and subjects enrolled in trials. 15 The member agencies on this group include 16 all those listed here -- AHRQ, CDD, OHRP, FDA, DoD, VA 17 and NIH. And at the first meeting of our task force, 18 we agreed upon three objectives. I'm going to show 19 you those on the next three slides but I'm here today 20 to report to you a major deliverable. I'm going to 21 focus on one of these objects for the remainder of the 22 talk, but let's go over the three objectives that were 49 1 agreed to: 2 The first objective was that the agencies 3 will speak the same language. Many of you know that 4 there is a whole lexicon of varied terminology out 5 there for dealing with safety information. Examples 6 include the terms, "unanticipated, unexpected, related 7 versus associated, immediately versus as soon as 8 possible, adverse event versus unanticipated problem." 9 The task force has spent the better part 10 of the last year conducted an in-depth inventory of 11 all of the terms, definitions and policies that we in 12 the federal government use when we talk about safety 13 information and create policies in this arena, and 14 we've mapped those terms across the spectrum. 15 Are they rooted in regulation and the code 16 of federal regulation or are they rooted in documents 17 that have some regulatory teeth but aren't regulations 18 per se. For example, ICH E2B, which is an agreement 19 to international conference on harmonization, endorsed 20 by regulatory agencies around the world. It has some 21 force but it's not equivalent to the U.S. code of 22 regulations. 50 1 Or are these requirements, in terms and 2 definitions, rooted in guidance or policy of an 3 individual department, or agency within that 4 department, or even a division or program in a 5 particular institute or agency? 6 And you can see that by mapping out where 7 these terms and policies derive, we can create a 8 spectrum on those things more difficult to change, to 9 things that may be closer to the ground, more amenable 10 to change. 11 The good news here is that many of the 12 terms and definitions that differ significantly among 13 the agencies and departments actually are rooted in 14 guidance and policy; they are not rooted in 15 regulation. And therefore, we believe they are 16 amendable to alignment and I look forward do coming 17 back and reporting to you on our proposals in this 18 arena at a future time. 19 The second objective that the task force 20 agreed upon was that we would carefully examine each 21 agency, conduct an exercise in introspection within 22 its own activities. Look at carefully the information 51 1 we collect, how do we analyze when we get it and then 2 what do we do with it? 3 Then we would meet and talk about what are 4 best practices? What are critical control points in 5 that workflow process? With an eye toward developing 6 best practices, to optimize information flow, the 7 concept of utilizing controllable vocabularies to 8 support analysis and also to promote standardized 9 reporting at the local level to IRBs and DSMVs. And 10 again, I look forward to coming back and talking to 11 you about this aspect of our activities. 12 What I'm going to focus on today is this 13 third objective. We hoped and articulated the goal at 14 our first meeting that one core adverse event could be 15 developed, the PIs could use, principle investigators 16 could use to submit to multiple agencies. And we 17 dubbed this the Basal Adverse Event Report, otherwise 18 know as the BAER. 19 The features of the BAER would be that it 20 would contain a baseline set of core information, 21 administrative and medical that could be adopted by 22 all agencies. We didn't set out to reinvent the wheel 52 1 here; we thought it was important to build upon 2 ongoing initiatives within HHS with regard to 3 standards, and for data transmission and vocabularies 4 in the healthcare sector. 5 We also had our eye on the goal of 6 developing something that could also be used to report 7 unanticipated problems. 8 I want to say a word here about our 9 process and activities. This group has been 10 extensively engaged in a series of focus groups within 11 each agency. With staff who on a day-to-day basis are 12 dealing with safety information, and we've developed, 13 have finished developing them -- the draft products. 14 The unified lexicon, best practices in workflow and 15 the Basal Adverse Report. 16 We also conducted some limited outreach to 17 stakeholders. We've met with about 35 IRB chairs and 18 administrators. We've met with groups of principle 19 investigators and clinical research coordinators 20 engaged in running some very large multi-center trials 21 across the nation. 22 And we had begun to dialog with industry 53 1 primarily through two organizations that already exist 2 and are very busy developing standards for handling 3 healthcare and health research information known as 4 health level 7 and CDISC. And those of you who are 5 the well-versed in the area of standards development 6 will recognize the important role that these two 7 organizations have. 8 In going about our work we have not only 9 looked at the various forms, and those of you who are 10 among you who are the cognoscenti of dealing with 11 adverse events and safety information, will recognize 12 some of these terms shown here in small print on the 13 left-hand side of the screen. ICH2B, there's various 14 CDC forms, MedWatch among others. 15 In addition to looking at the forms we 16 spend a lot of time meeting and talking with the 17 agencies about their data requirements, their needs, 18 what do they need to do their job with regard to 19 protecting human subjects and analyzing adverse-event 20 reports. 21 What resulted was a universe of about 22 4,000 date elements that the federal government 54 1 currently collects in terms of safety information. 2 Returning back to those agencies and talking about how 3 the various concepts and elements report from one 4 agency to another we discovered a great deal of 5 redundancy -- that they're the same underlying 6 concept, but they are termed different things, and 7 that universe can be reduced to approximately 300 core 8 data elements. I want to speak a little bit more 9 about the composition of those data elements. 10 That universe of roughly 300 data elements 11 has a subset which I like to term "static data 12 elements." Right now the BAER is a listing or a 13 description of the data elements that need to be in a 14 safety report. It is not a software program but it is 15 envisioned that ultimately this would be a program 16 that an investigator could sit down in front of his 17 screen and pull up those data elements that are 18 relevant to his or her trial. 19 Of those data elements, a subset -- 20 roughly 40 -- are so-called static. You enter them 21 once, as long as you hit the "save" button you don't 22 have to enter them again. It's the name of the PI, 55 1 the trial site, the nature of the intervention. 2 The other element are what I like to call 3 the "dynamic data elements." These will change 4 according to the specific event at hand and will also 5 be dictated, of course, by the nature of the trial. 6 Is it an interventional study? Are you using the drug 7 a biologic a device or another type of behavioral 8 intervention, or is it an observational study? Is 9 this an epidemiologic surveillance natural history 10 study? 11 And we took a lot of care to make sure 12 that the BAER was analyzed through the eyes of those 13 who are engaged in observational research, not only 14 through the eyes of those engaged in typical 15 interventional studies using drugs or biologics. 16 We also took care to meet extensively with 17 OHRP and also other agencies that required the 18 reporting of unanticipated problems, so a subset of 19 the 300 data elements covers unanticipated problems. 20 Does this mean that every time an investigator wants 21 to report an adverse event they have to fill out 300 22 data elements? No. And I want to be clear about 56 1 saying that. 2 You will pull up -- and I want to show a 3 few mock screens of what this might look like -- you 4 would pull up a screen, pull out your administrative 5 data study information. If you're doing a drug trial, 6 a subset of those elements will come out and depending 7 on the particular nature of the trial, the study 8 designed in the event that you're trying to describe, 9 it will be a subset of that 300, perhaps 70 or 80, as 10 an example. And again, if you're doing a device trial 11 there will be some unique elements that would come 12 forward for you to fill out if you're doing the device 13 study and unanticipated problems, likewise. 14 So key features of the BAER as it's 15 currently conceptualized is that it draws upon 16 existing standards for adverse event reporting. Those 17 of you familiar with ICH E2B, it's incorporated into 18 there. Those of you familiar with FDA and industry's 19 work with health level 7 in developing the individual 20 case safety report, the ICSR in included in the BAER. 21 The BAER also importantly encompasses 22 behavioral and social science's research, 57 1 epidemiologic and surveillance studies as well as 2 health services research. Investigators will be able 3 to draw upon a single streamlined data-set to report 4 safety information to multiple agencies, again, 5 customizing the view for the particular study at hand. 6 They'll be able to use it to report unanticipated 7 problems and it could be used potentially to report to 8 IRBs and DSMBs. 9 Most importantly, the BAER has the 10 potential to enhance the protection of human subjects 11 by providing standards that will enable more uniform 12 and streamlined approach to adverse event reporting 13 and we believe this will promote completeness of data, 14 it will improve the quality of the data and 15 importantly, facilitate the analysis of that 16 information. 17 The current status of the BAER is that the 18 task force members, conferring with leadership in 19 their agency agree that the draft BAER represents a 20 single baseline core, set of information acceptable to 21 their agency. That is contains information needed for 22 adverse event and unanticipated problem reporting 58 1 across all types of clinical research. 2 The next steps, the first one: We're here 3 today, briefing this Committee and eager to have your 4 feedback. We need to further engage the user 5 committee and toward that end we'll be developing some 6 views of the data-sets so that people can see what it 7 would be like to actually use a system that relies on 8 the BAER. 9 And we will look forward to target 10 implementation. Maybe it's a bit ambitious, but we're 11 hopeful of 2007 and if you would like some more 12 information, we have a great deal more information on 13 our website, and I'd also like to acknowledge my 14 colleagues at the various agencies, the project 15 officer, Kelly Fennington who has worked extremely 16 hard on this project, and then the entire contractor 17 staff at Stellar has done an amazing job. Thank you. 18 DR. PRENTICE: Thank you. We appreciate 19 it. We're going to hold questions if that is 20 acceptable to everybody until we've had our second 21 presenter, Dr. Mike Carome. 22 While Dr. Carome is coming up to the 59 1 front, I will tell you just a little bit about him. 2 Again, he doesn't need any introduction like Amy 3 Patterson as well. 4 Dr. Carome is a captain in the U.S. Public 5 Health Service. He is the associate director for 6 regulatory affairs at OHRP. He is also a staff 7 nephrologist at the Walter Reed Army Medical Center, 8 Department of Medicine. So Michael, welcome and thank 9 you for agreeing to talk to us today about the OHRP's 10 draft guidance on reporting and reviewing adverse 11 events and unanticipated problems. 12 DR. CAROME: Thank you, Ernie. It's a 13 pleasure to be here again and give the Committee an 14 update on OHRP's development of its draft guidance on 15 this important topic and this is an activity that's 16 occurred in parallel and intricately involved with the 17 task force that Amy just went over. 18 What I'd like to do quickly, in about 19 seven or eight minutes, just quickly remind the 20 Committee of some background information about how we 21 go to where we are now, give an overview of public 22 comments that we've received on the draft guidance and 60 1 then talk about next steps, and then we'll open it up 2 for broader discussion with the Committee. 3 So in terms of some key background items, 4 in March of 2004 this Committee passed a resolution 5 recommending that OHRP and FDA promptly issue clear 6 and consistent joint guidance on IRB review of both 7 internal and external adverse event reports that will 8 best serve to protect human subjects and effectively 9 reduce regulatory burden. 10 The emphasis on external adverse event 11 reports is my add. The Committee heard, through a 12 series of panels involving the IRB and research 13 community how IRBs were being inundated with large 14 volumes of external adverse event reports, and that 15 was much of the burden they felt needed to be 16 addressed. 17 In the wake of that recommendation by this 18 Committee, there was formation of the Federal Adverse 19 Events task force formed from among the ex officio 20 members that sit and represent the Committee in that 21 group, as Amy just talked about, is chaired by NIH. 22 Subsequent to that recommendation OHRP 61 1 prepared a draft guidance document on the reporting 2 and handling of unanticipated problems and adverse 3 events. Several iterations of the guidance before it 4 was released to the public was shared with members of 5 the task force that Amy leads, and with other common 6 rule departments and agencies. 7 The document then was posted for public 8 and review on our website back in October of 2005. 9 That document is in your briefing books if you haven't 10 seen it; it's at tab H. And the common period given 11 the length of the document and the importance of the 12 topic, there was a three-month commentary that closed 13 in January of this year. 14 Just to briefly remind you about the 15 organization of that guidance document, it was divided 16 to ten sections, each of which was a question, and 17 those were briefly: What are adverse events? What 18 are external and internal adverse events? What are 19 unanticipated problems and how do they relate to 20 adverse events? How do you determine which adverse 21 events are unanticipated problems that need to be 22 reported under the HSS regulations at 45CFR part 46? 62 1 What should the IRB consider at the time of initial 2 review with respect to adverse events? 3 The last set of five topics were: How 4 should reports of external adverse events, internal 5 adverse events and unanticipated problems be handled? 6 What is the appropriate time frame for reporting 7 unanticipated problems to the IRB, to institutional 8 officials and to appropriate agencies including our 9 office? What should the IRB consider at the time of 10 continuing review with respect to adverse events and 11 unanticipated problems? What interactions should 12 occur between IRB and data safety monitoring boards or 13 data monitoring committees with regard to adverse 14 events and unanticipated problems? And finally, what 15 should written IRB procedures include with respect to 16 reporting of unanticipated problems? 17 So I'd like to now turn very briefly, 18 review the scope of the comments that we received. We 19 received a lot of comments, and it's hard to give 20 justice to all the comments we received so this is 21 very -- it's sort of some highlights. 22 We received comments from a total of 54 63 1 individuals and/or organizations and of those, 26 were 2 organizations that included research institutions, 3 IRBs, academic organizations, human subject advocacy 4 groups and patient advocacy groups. We received a 5 separate set of comments from 28 individuals which 6 included IRB members, research investigators, 7 institutional officials and consumer advocates. 8 In terms of some general comments or 9 statements made in these comments, 35 comments were 10 explicitly supportive of the guidance and of those, 19 11 were strongly supportive. Fifteen included no general 12 statement about support or non-support, but given sort 13 of the minor edits they were suggesting, we presumed 14 they were supportive, and four were not supportive of 15 the document. 16 The most frequent general comment which 17 was made by 15 of the commenters called for joint 18 harmonized guidance from OHRP, FDA, NIH and the other 19 federal agencies. 20 I'm now going to just highlight some of 21 the comments with respect to some specific sections. 22 I won't go through all the sections, but the first 64 1 section: What are adverse events? Seven commenters 2 addressed this area of the document and several 3 recommended inclusion of a clear definition of the 4 term "adverse event," as well as inclusion of 5 definitions of the words "serious,"harm," and 6 "discomfort." 7 Section three: What are unanticipated 8 problems and how do they relate to adverse events? 9 This is was the section for which there was most 10 frequent comment upon -- 22 commenters addressed this. 11 Several again recommended some additional definitions, 12 including the definitions of "serious," "non-serious," 13 and the term "possibly related." 14 Several recommended that for adverse event 15 assessments the term "related" or "possibly related" 16 which was used in the document for classifying adverse 17 events, should be changed to either "probably related" 18 or "definitely related." And one commenter 19 recommended inclusion of a decision chart for 20 classifying adverse events and unanticipated problems. 21 On terms of section 5, what should the IRB 22 consider at the time of initial review with respect to 65 1 adverse events? Nine commenters addressed this 2 section of the document and two commenters in 3 particular recommended that the guidance stated more 4 strongly that monitoring plans should be adjusted to 5 fit the degree of risk of the research; the more the 6 risk, the greater monitoring or the more intensive 7 monitoring should be included. 8 On section 6, how should reports of 9 external adverse events and internal adverse events 10 and unanticipated problems be handled? Nineteen 11 commenters addressed this section of the document. 12 Some commenters suggested that external adverse 13 events, which again represents the greatest burden to 14 IRBs, that represent unanticipated problems should not 15 need to be reported beyond the IRB for each site. So 16 the IRB gets it and it doesn't go to other 17 institutional officials or other institutional 18 entities with any agency beyond that IRB. 19 Two commenters recommended that the 20 guidance address circumstance in which an IRB wants to 21 change a protocol in response to an unanticipated 22 problem, but the sponsor disagrees with the proposed 66 1 changes. 2 Section 7, what is the appropriate time 3 frame for reporting unanticipated problems to various 4 entities? Seven commenters addressed this section and 5 the most frequent from several of them was a 6 recommendation that guidance include a clearer 7 definition of "prompt" and include more specific time 8 frames for reporting. 9 So that's, again, a very quick overview. 10 There are other important comments that I haven't 11 addressed in that review. So what are the next steps? 12 In response to the comments, and I will also note that 13 simultaneous with receipt of the public comments we 14 got a set of comments from the FDA who were working 15 closing with this on these efforts, and in response to 16 the public comments and those from FDA we have taken 17 an effort to significantly revise the document. 18 We found many of the comments to be very 19 helpful. They raised some very important points and 20 to the extent that we can draw some clearer lines 21 about what should be reported and what not, we're 22 trying to do that in response to the comments. 67 1 The second step after doing those 2 revisions is to consult with the FDA and I'll tell you 3 that step has already occurred and there will be 4 additional consultation from FDA as we progress 5 through iterations of the draft. 6 We're then going to, in the near future, 7 consult with other representatives of the Federal 8 Adverse Events task force, share the document with 9 them and let them react to it and propose additional 10 edits. 11 Beyond that, we are going to then consult 12 with other common rule departments and agencies. 13 Again, many sit as ex officio members to this group. 14 And then hopefully we'll close out with issuing final 15 revised guidance on this topic. And again, that final 16 guidance may not be final. This is, again, an area of 17 revolution and as we get additional feedback on that 18 final "document" the document may further evolve as we 19 work both with other government departments and 20 agencies and members of the public who inevitably will 21 react to the document. So thank you for your 22 attention and I'll open it up for questions and 68 1 discussion. 2 DR. PRENTICE: Thank you, Mike. Dr. 3 Patterson, come up to the table, please? Okay. For 4 the old SACHRP members you know that I exercise 5 chairman's prerogative to ask for a few question, so 6 now the new members know that that's what we do with 7 your indulgence. As I often say, this is the only 8 advantage that I have to being chair of this August 9 body. 10 I'll begin with Amy. Your BAER system, it 11 would seem like it resembles GEMCRIS to some extent. 12 Would that be a fair observation on my part? 13 DR. PATTERSON: It does resemble GEMCRIS. 14 There are some modifications that need to made in 15 GEMCRIS to align it with the BAER. The BAER is not 16 exactly the same as GEMCRIS and the reason for that is 17 that as those of you may already be familiar with 18 GEMCRIS know, GEMCRIS is the Genetic Medical Clinical 19 Research Information System that NIH and FDA developed 20 jointly for reporting adverse events on gene transfer 21 or gene therapy clinical trials and it's been in 22 operation several years now. 69 1 Because that database and the core data 2 elements there were developed primarily for gene 3 transfer trials and were developed as a product of NIH 4 and FDA, it does not include some of the other 5 elements that other agencies felt might be important 6 and certainly doesn't include some of the elements 7 that would be important, say, for device trial or 8 another type of intervention. So there are a few 9 accommodations that need to made in GEMCRIS, but it's 10 quite similar. 11 DR. PRENTICE: Okay. I guess that leads 12 me to my next question. The number of active gene 13 transfer trials in the United States I think is what? 14 One hundred and something? Somewhere around there? 15 DR. PATTERSON: It's a little bit more 16 than that, but many 120, 130. 17 DR. PRENTICE: 120, 130. And I would 18 assume that we're talking about a significantly larger 19 number of clinical trials that would feed into this 20 database. Would that be a fair assumption? 21 DR. PATTERSON: Right. I should clarify 22 that at the moment we're not envisioning that there is 70 1 a single database that all trials are reporting into 2 under the BAER, but rather, right the BAER is an 3 agreement among the agency of what needs to be in a 4 report to their agency that could also be submitted to 5 others. 6 The next step would be to develop software 7 applications that could make that report interactive 8 useable on a computerized interface. Ultimately one 9 could envision a centralized registry of all adverse 10 events among all the agencies but that is not 11 currently on the table. So I just want to clarify, 12 whereas GEMCRIS is a unified database for all gene 13 therapy trials and includes all the trials ever 14 conducted in this country, active or inactive. 15 DR. PRENTICE: Okay. So the database 16 would be maintained by each agency and the IRBs would 17 report, or the investigators would report to that 18 agency and the data would be entered. And they could 19 then, in turn, access that data, right? Is that the 20 way it works? 21 DR. PATTERSON: Well, ultimately, but 22 right now, where it is right now is an agreement upon 71 1 what's reportable, whether there's a centralized 2 repository is I think an issue for discussion. 3 DR. PRENTICE: Okay. You mentioned at the 4 beginning of your presentation trying to harmonize the 5 language, and you gave some examples. You also talked 6 about thresholds for reporting adverse events, and I 7 would assume that means reporting to the IRB and of 8 course reporting to the agencies. And I guess my 9 question is for both of you: Mike, you referred to 10 internal versus external adverse events and in reading 11 the guidance, if I read it correctly, the 12 recommendation is that normally the IRB where the 13 adverse event occurred, the site where it occurred, 14 would be the IRB that reports to OHRP and FDA. 15 When an external site gets an external 16 adverse event, we would not be obligated under normal 17 circumstances to report. So I think I understand 18 that, but the basis of my question is, is there a 19 difference in threshold reporting for internal versus 20 external adverse events because you keep on referring 21 to serious adverse events, and I know that there are 22 IRBs out there that have that threshold reporting for 72 1 internal adverse events. In other words, if it's not 2 serious, if it's not associated or related, or 3 possibly related with the research, and if it's not 4 unanticipated or unexpected, it never even gets to 5 that local IRB. And in reading your guidance document 6 it was unclear whether or not you had a lower 7 threshold of reporting at the local level. Could you 8 perhaps comment on that? 9 DR. CAROME: Sure. We do not have a 10 different threshold for whether something -- whether 11 an event is an unanticipated problems based upon 12 whether it's an external or internal event. Just from 13 a logical standpoint that would be difficult, I think, 14 to justify. 15 What's different is who does the report 16 need to flow to if you're an institution where 17 something occurred internally versus you've got this 18 external event reported to you, and it doesn't need to 19 flow to anyone else but the IRB if it's an external 20 adverse event report that was determined to be an 21 unanticipated problem. 22 But the threshold for what a particular 73 1 event is, you should be able to apply a definition, 2 regardless of whether it was external or internal. 3 The event itself taken outside of the external or 4 internal context doesn't meet an unanticipated problem 5 or not. It's then a matter of who does it need to be 6 reported to and who does the reporting. 7 DR. PRENTICE: So you note some criteria 8 for what is an unanticipated. You have some criteria 9 for when an internal adverse event is an unanticipated 10 problem involving risk, right? 11 DR. CAROME: I think the criteria for 12 what's and unanticipated problem does not differ from 13 whether it's external or internal. 14 DR. PRENTICE: Okay. 15 DR. CAROME: But how it's handled, you 16 know, who it flows to differs slightly. And we tried 17 to, again, the comment you're raising is along the 18 lines of some of the other commenters and we try to 19 clarify the point you're raising in the next draft. 20 DR. PRENTICE: Okay. So I assume that 21 then you're going to clarify what an altered risk- 22 benefit relationship means? Is that where we're going 74 1 Altered risk-benefit relationship is a consequence of 2 the adverse event? 3 DR. CAROME: We're considering actually 4 changing that concept slightly so it's clearer. 5 DR. PRENTICE: Okay. Because I guess 6 where I'm going -- and this will be last question or 7 perhaps my last comment -- I'm real concerned about 8 having an appropriate risk threshold level of 9 reporting at the institutional level, and if you look 10 at the kinds of requirements for disclosure in the 11 consent document, routine venipuncture, you've got to 12 disclose the risks of, you know, pain, possibility of 13 infection, etc. -- hematoma. I mean, that's pretty 14 minor -- a venipuncture is pretty minor; those risks 15 are pretty minor. 16 I would hate to think that the guidance 17 that's issued by OHRP and FDA that gives institutions 18 an opportunity to say, "Well, you know, the only thing 19 that has to be reported to the IRB when there's a 20 adverse event is something that's pretty darn 21 serious." There's got to be a lower-risk threshold or 22 a lower-harm threshold, if you will. 75 1 DR. CAROME: Yes. I think we are in 2 complete agreement, so there are adverse events either 3 group or series of them or in some cases an individual 4 one which don't rise to the level of "serious," and we 5 were asked actually one of the comments was for us to 6 define what "serious" is -- 7 DR. PRENTICE: Right. 8 DR. CAROME: But say you apply the FDA's 9 definition of "serious." We believe that there are 10 adverse events that don't meet that definition -- 11 DR. PRENTICE: That need to be reported. 12 DR. CAROME: -- that would be considered 13 unanticipated problem and should be reported. 14 DR. PRENTICE: Okay. 15 DR. CAROME: And the document will try to 16 clarify that group very clearly. 17 DR. PRENTICE: Okay. Great. All right. 18 Would you please raise your hands and I will write 19 down your names in order. I saw Neil was first. I 20 think Susan was second and Dan was third. Neil? 21 DR. POWE: Dr. Patterson, I was wondering 22 in the future plans for the BAER, are there plans for 76 1 pilot testing this in the user community and what's 2 the extent of those plans? 3 DR. PATTERSON: Absolutely. If I showed 4 you the BAER right now you'd think it's pretty ugly. 5 It's a line-listing of all the data elements and it's 6 not very user-friendly, so over the next several 7 months what we are going to try to do is to develop 8 some mock-up screens that would allow -- and the 9 software behind them to support them -- that would 10 allow investigators, clinical research coordinators 11 out in the field to actually use the system. To sit 12 down and say, "Okay. I'm getting funding from MIH or 13 the VA. I'm doing a drug or biologic trial." Enter 14 in those parameters and have the data-set come forward 15 that they need to complete for that trial and to 16 exercise the system. 17 We also are looking for opportunities to 18 present to groups of institutions what the concept is 19 here, what the goals are and also make the system, 20 when it's developed, available for BETA testing well 21 before we would put it forward in final form. It 22 needs a lot of exercise. 77 1 DR. PRENTICE: Susan? 2 DR. WEINER: Actually, my question is also 3 for you, Dr. Patterson, and it's related to the 4 usability but it's one step prior and that really has 5 to do with the notion of the validity of the 6 instrument itself. If it represents, you know, 7 conceptual reduction of 300 elements -- 4,000 and once 8 300 -- among 6 or 7 agencies, do you plan to take 9 steps to essentially validate the instrument with 10 respect to the individual agencies so that there is 11 some reassurance that the culture of and the 12 priorities of that particular agency are met? 13 DR. PATTERSON: That's a very important 14 question and sometimes when I hesitate to show the 15 slide of 4,000 to 300 because one could ask the 16 question, "Well, you know, is this a step backwards 17 that we're actually stripping away protections or 18 we're losing information?" That reduction is 19 primarily a reflection of the elimination of 20 redundancies among the various terms and conditions. 21 One of the best ways, I believe, to 22 validate or test the system will be able to run past 78 1 reports through, and it's also important to remember 2 that the BAER itself does not set policy; there's no 3 policy inherent in it. The threshold for reporting 4 the criteria for reporting are separate. What's in 5 the BAER is what's contained in the report, so whether 6 something fits the criteria for an unanticipated 7 problem is not dictated or determined by the BAER. 8 Rather, what's in that report, what OHRP wants to see 9 when they see an unanticipated report, or the VA 10 Administration, when they see an unanticipated report, 11 that's what you'll find in the BAER. 12 DR. PRENTICE: Dan? 13 MR. NELSON: Amy, I'm looking at your 14 penultimate slide on the handouts, the printed 15 handouts, that came out and couldn't help but notice 16 there was, along with your target of 2007, there was 17 a reference to initial voluntary adoption which I then 18 noted was absent from your slide, so maybe you've 19 rethought that point. 20 But I would like to just invite a little 21 discussion on how you see this being rolled out and 22 maybe what that referred to -- if it's the BAER tool 79 1 as opposed to the underlying policy structure, and I'm 2 speaking from a vantage point of just having made the 3 mistake of rolling something out and making it 4 voluntary just on our campus, and human nature and 5 bureaucratic inertia being what they are, of course, 6 everybody opted to maintain the status quo and I'd 7 hate to see that happen here. 8 DR. PATTERSON: Yes. No, I'm thrilled to 9 answer that question. I deleted it because I wasn't 10 sure how much discussion we would want to get into. 11 This -- what Dan is referring to is, I 12 deleted for this show, slide-show here, a bullet 13 that's actually on your printout that alludes to the 14 question of whether there would be initial voluntary 15 adoption rather than going out with the requirement, 16 and this is something that's actually under debate and 17 discussion within the FAE among the agencies. It's 18 something that, as we go through our public 19 consultation process that we're going to want a lot of 20 input on, there's sort of two schools of thought at 21 the extremes and probably of every permutation in 22 between. 80 1 But the two schools of thought here are, 2 do we go out with the BAER in initially voluntary -- 3 so say we go through the BETA testing, we got the 4 system approved, we institute it as a voluntary system 5 and really allow it to be exercised in a far broader 6 way than we could through any several-month or one- 7 year phase of BETA testing. Allow it to be adopted 8 voluntarily for probably a year, two, or three and get 9 the bugs, you know, further worked out. See whether 10 it really does address the needs or whether it needs 11 further development or enhancement. That's one school 12 of thought, that better that than impose something 13 that still needs work, and we won't find out what all 14 those bugs are until it's really widely deployed. 15 The other school of thought at the other 16 end of the spectrum is go through your BETA testing, 17 make a reasonable approach to what's needed here and 18 what serves the interests of the research committee 19 and human subjects, research subjects, and make it a 20 requirement, because only in that way will you enhance 21 the completeness and the quality of reports and really 22 get buy-in. Because there's going to be an activation 81 1 energy here to get people to change from the way 2 they're currently doing business to adopting this. 3 And I think that there are pros and cons 4 to both schools of thought and that's why, because 5 it's an under-discussion, I deleted it. But that's -- 6 and I'd be thrilled to hear your comments on the 7 school of thought you belong to. 8 MR. NELSON: I'd be interested in hearing 9 from the rest of the Committee, of course, but I 10 already alluded to my school of thought which shifted. 11 And again, I'm speaking just from having tried to roll 12 at a much smaller change on a single campus and, 13 again, human nature and just the bureaucratic 14 functional inertia, I realized six months later I was 15 just going to have to say, okay, now we're really 16 going to do it, because nobody's voluntarily buying 17 into this. 18 So I suspect that given the morass that 19 you're trying to address across the entire country and 20 all of those different forms you showed, and the 4,000 21 overlapping data points, etc., etc., and I think after 22 some appropriate BETA testing validation, pilot 82 1 testing, that you'd have to move to more voluntary, 2 mandatory approach. That'd be my two cents. 3 DR. PRENTICE: Now I'll throw in my four 4 cents. I totally agree that the institutional level 5 nothing works unless it's mandatory, particularly when 6 you're talking about this kind of activity. 7 You know, for example, if you're going to 8 roll out an electronic version of IRB application, 9 would you give people a choice? You know, some people 10 might choose it; other people are not going to choose 11 it. It just doesn't work, so I would encourage you to 12 have a discussion along those lines because it would 13 make it much more effective, I think, if you make it 14 mandatory. Jeff, you're up next. 15 DR. BOTKIN: I wonder if there are 16 evidence-based performance measures for the system 17 that will help assess this process as it goes on and 18 obviously some of the outreach has been satisfaction 19 or dissatisfaction surveys. But obviously ultimately 20 the point is to identify true positives through the 21 system, however defined, and eliminate or reduce the 22 false negatives and the false positives. 83 1 So I guess the question is: Do we have a 2 sense of what those numbers look like now and as this 3 system goes into place, if it's either more or less 4 effective, will you actually be able to determine 5 that? 6 DR. PATTERSON: We've actually begun to 7 give some thought to this. It is in essence the issue 8 of end points -- what are the end points? How will we 9 know if this has been successful? How will we know if 10 the world is a better place as a result of BAER or 11 not? 12 It's a very important question. 13 Unfortunately, I don't think that, short of doing a 14 study right now in the design of that study, I think 15 there's a lot of careful thought. I'm not sure that 16 we have a good baseline and I think that's going to be 17 important to establish, and certainly welcome the 18 Committee's and your thoughts if you want to talk 19 offline about this, but it's clearly something that's 20 on the table and part of the development plan is to 21 have end points here. 22 DR. PRENTICE: James? 84 1 DR. POWELL: Mike, I think one of your 2 comments was regarding research institutions had 3 commented on this document and I wondered if it 4 included private industry sponsors as well? 5 DR. CAROME: Yes. We got comments from 6 AvaMed and one other industry group commenting on 7 behalf of the research industry, the private sector, 8 yes. 9 DR. POWELL: I would imagine having 10 several databases with information on adverse events 11 would have a real impact on industry knowing where 12 those adverse events are and how to search it and what 13 impact it might have on the products that they may be 14 developing or have on the marketplace, or even their 15 labeling. 16 And so one of my question, I think you 17 mentioned also that as you collect the information it 18 will be open for anyone to search even if you -- I 19 think you said you are not going to do a centralized 20 at the beginning, but at some point people will have 21 the ability to search adverse events? 22 DR. PATTERSON: Well, right now, no, we 85 1 haven't conceptualized a system where there's a 2 central repository that anyone would be able to 3 search. This is a system that's designed for -- well, 4 it's not even a system yet; it's an agreement upon the 5 content of the reports to the federal agencies. 6 I can tell you, though, that from our 7 experience in the world of gene transfer or gene 8 therapy, which traditionally has been perhaps an 9 outlier in terms of other avenues of clinical research 10 insofar as that it's been developed in a fairly 11 transparent fashion, the design of the trials is 12 publicly available. 13 The adverse events that occur in these 14 trials are reported on quarterly in a public meeting 15 of an advisory committee akin to this. And when we 16 develop the adverse event database system for gene 17 therapy trials, there is a public face of that. It 18 does not include all the details that the medical 19 officers within the agency would be viewing, but it is 20 possible for people who are interested in following 21 the field perspective subjects other people engaged in 22 the industry RND to go and look up and see what events 86 1 have occurred on a trial, perhaps using a product 2 similar to the one that they are developing. 3 Right now the work of the FAE has not been 4 conceptualized as providing a centralized database 5 with a public side of it. As I think many of you 6 sitting here will know, both at the table and in the 7 audience, there are again pros and cons of doing that. 8 The pros are enhancing knowledge and 9 awareness and hopefully preventing similar events in 10 the future. Some of the cons about making information 11 like that publicly available has to do with the timing 12 of when it's made available. Sometimes when you get 13 a report, an initial report, when the data comes in 14 the attribution changes. It wasn't due to the 15 intervention; it was due to underlying disease or a 16 combination. 17 So it's hard to know sometimes how to 18 respond to those events when they come online. So 19 there are many important questions like that that have 20 to be considered before you make information widely 21 available. I could go on a long time about that, but 22 I won't. 87 1 DR. PRENTICE: Okay. Last question. 2 Celia? 3 DR. FISHER: First of all, I think it's 4 wonderful the way you're putting together something 5 that can be harmonized and trying to -- certainly I 6 think the definitions are going to be incredibly 7 important once you do it. 8 I had a number of questions, of course, 9 but -- 10 DR. PRENTICE: You can only have one. 11 DR. FISHER: Right. Right. So I'll put 12 it together as a package. 13 (Laughter) 14 DR. FISHER: One area of concern in this 15 whole series of questions has to do -- and I think, 16 Amy, you were really getting at it -- in terms of how 17 do you have a useful database that does not 18 overemphasize some unanticipated events that may, over 19 the course of time, not be associated with the 20 interventions themselves which I think is always a 21 problem with a database. 22 The other is, in terms of Ernie's 88 1 questions, I understood as we first began to be 2 talking about this as a board, that one of the 3 critical issues was to, in some sense, reduce 4 unnecessary burden on the IRBs. At the same time, it 5 occurs to me that anticipated adverse events, when the 6 IRB is paying attention to them, can really point to 7 incompetence on the part of the investigator with 8 respect to why are all these anticipated events coming 9 up, you know, with a frequency that should not be 10 there, just as with the blood-draw. 11 And so in terms of how we reduce burden 12 but maintain local subject protection with respect to 13 these events is a question I have. 14 And then finally, how one is going to 15 require or insure that independent IRBs are going to 16 be participating in this kind of reporting? 17 DR. PATTERSON: So I have the database 18 issue that the seesaw, decreasing burden but making 19 sure that we don't lose protections and awareness of - 20 - we don't have things drop off the radar screen that 21 might be anticipated and that occurring at a frequency 22 that is above what the previous experience with that 89 1 product or intervention would lead us to anticipate, 2 and the third issue is the involvement of independent 3 IRBs. 4 First of all, with regard to the database 5 I want to back up and perhaps I'm at fault here for 6 having shown you some mock screens, because the first 7 step here in harmonizing and streamlining is to reach 8 an agreement on what is needed to understand what has 9 happened to this human subject and what are the 10 appropriate followup events. 11 And right now we have a system where the 12 quality of information is quite varied, often 13 incomplete, and therefore wise and appropriate 14 decisions are not easy to always reach. So this 15 effort is really aimed at coalescing the agencies 16 together on a common view of what needs to be in that 17 report. And by virtue of streamlining and 18 standardizing the report, it facilitates the 19 development at the local level and the federal level 20 of databases that could compare events within a trial, 21 across trials, but right now this isn't a centralized 22 database and ignores a centralized database and Mike, 90 1 help me out here, is not necessarily the aim of this 2 effort. 3 Secondly, again with regard to decreasing 4 burden, we hope the BAER will do that. It still does 5 not set policy. You could have a local policy that 6 sets the threshold for what's reportable to your IRB 7 wherever you want it -- high or low. 8 The BAER is a mechanism or vehicle for 9 reporting that information to the IRB. The setting of 10 the threshold is going to come through in the policy 11 work, partly for example, in the document that Mike 12 and his team have been working on. 13 With regard to the engagement of 14 independent IRBs in assignment, I am hopeful that they 15 will see this as an asset and a step forward, the 16 standardization of reporting, and particularly if we 17 go the required route, as Dan was suggesting, I think 18 it will end up being mandated, but -- Ernie? 19 DR. PRENTICE: Okay. Thanks very much. 20 I would like to conclude by thanking both of you and 21 all your Committee members for all the hard work. As 22 Mike indicated in his background slide, this was a 91 1 SACHRP resolution passed at the March 2004 meeting 2 that asked that you work on this particular problem. 3 You have periodically come back to SACHRP and reported 4 on the progress, and I think this is a clear 5 indication that we thought this was a problem that 6 needed to be resolved, and you've taken it seriously, 7 and you're working diligently to solve the problem. 8 Many of us in the IRB world have known 9 about this problem since, oh, probably the 1990s and 10 nothing has really happened until 2004, so we're 11 delighted with the work and we look forward to future 12 reports from you. So thanks very much. 13 Now we're going to take a break. We are 14 exactly seven minutes behind so we're going to cut the 15 break back by three minutes, so if you would please 16 assemble twelve minutes from now, which would be 17 10:17. 18 (Whereupon, a short break was taken.) 19 DR. PRENTICE: All right, folks. If we 20 could reassemble, please. Okay. Before we begin I 21 have some announcements. First, we all need to speak 22 into the microphones because the recorder is having a 92 1 difficult time picking up some of the voices. So if 2 you would, that would be appreciated. 3 Secondly, as you know, we're going to have 4 a working lunch with some ethics training. Lunch will 5 be provided for SACHRP members. Unfortunately, lunch 6 will not be provided for non-SACHRP members, so that 7 means that the rest of the audience has to leave the 8 room. Apparently there's some sort of rule that says 9 you can't be around when we go through this ethics 10 training. So I apologize for that, however, there's 11 a very good restaurant here. 12 Third, we are going to reserve a table 13 here in the dining room at the L'Ameritage Restaurant 14 at 7:00 p.m. We'll canvass everybody at lunchtime to 15 find out whether or not you would like to dine in this 16 hotel. Your alternative is to go outside in 98-degree 17 weather and take a shuttle to some other restaurant 18 that's probably not as good, but this being a 19 Democratic Committee, you have that option. 20 Okay. Now we're going to ask Felix Gyi 21 and Dan Nelson, the co-chairs of our subpart A 22 subcommittee to present to us their recommendations. 93 1 Now, I want to indicate before they begin that many of 2 the recommendations that they are going to overview 3 have already been acted upon by SACHRP, so it's not 4 our intention to re-discuss those recommendations 5 unless someone looks at something and has a 6 significant problem with it. Then, of course, we'll 7 open it up for discussion. 8 Other than that, we have already discussed 9 these recommendations so they do not warrant 10 reconsideration unless it's extenuating circumstances. 11 And Dan and Felix will indicate to you very clearly 12 which ones have been approved by SACHRP, all right? 13 Okay. 14 MR. NELSON: Thank you, Ernie, and let me 15 start by saying how pleased I am to have Dr. Gyi still 16 sitting here next to me. Not only sitting here next 17 to me, but as an active co-chair of this subcommittee. 18 As you know, Felix rotated off the parent 19 subcommittee, SACHRP, but we're pleased to have him 20 and several other of our colleagues still remaining on 21 the subcommittee and taking an active role. 22 A brief outline of today's presentation, 94 1 you've already heard the subcommittee charge and our 2 membership from Dr. Prentice. Then, as Ernie said, 3 recommendations already made to SACHRP will be 4 reviewed and we're doing this for at least three 5 reasons, but we'll definitely not be re-reviewing all 6 recommendations. 7 Some of them you heard last night during 8 the orientation for new members, but we thought it 9 would be useful, especially for our new members, but 10 also for returning members to hear and see these in 11 more of a global context sort of providing this 12 overview in context and background. And also, there 13 were some selected revisions that you asked for and 14 that our subcommittee has returned with small 15 clarifications and again, we will point out those and 16 ask for your endorsement or discussion on those. 17 We will then present some recommendations 18 you haven't seen yet on the topic of expediter review 19 which will be our final installment on that topic, and 20 then we would close by asking for some marching orders 21 as to next topics