1 1 Department of Health and Human Services 2 3 4 Meeting of the 5 NATIONAL HUMAN RESEARCH PROTECTIONS 6 ADVISORY COMMITTEE (NHRPAC) 7 8 Monday, July 30, 2001 9 10 11 12 13 14 15 16 The DoubleTree Hotel 17 1750 Rockville Pike 18 Rockville, Maryland 20852 19 20 21 22 2 1 A G E N D A 2 3 Monday, July 31, 2001 4 5 8:30-8:45 Department of Health and Human 6 Services & Human Subject Protections 7 Arthur Lawrence, Ph.D. 8 Acting Principal Deputy Assistant 9 Secretary for Health 10 11 8:45-9:15 The Perilous Intersection of 12 Protecting Human Research Subjects and 13 Conflicts of Interest 14 Michael Wood, M.D. 15 President and CEO, The Mayo Foundation 16 17 9:15-9:30 WELCOME: Overview of Meeting 18 Mary Faith Marshall, Ph.D. 19 Chairperson, NHRPAC 20 21 22 3 1 9:30-10:30 Final Review & Approval of NHRPAC 2 Response to Financial Relationships 3 Mark Barnes, J.D. 4 Chairperson, Working Group 5 6 10:30-12:30 Update: Children's Workgroup 7 Alan Fleischman, M.D. 8 Chairperson, Working Group 9 10 10:15-10:30 BREAK 11 12 12:00-1:30 LUNCH (On your own) 13 14 15 16 17 18 19 20 21 22 4 1 1:30-3:30 The Office for Human Research 2 Protections (OHRP) 3 Introduction 4 Greg Koski, Ph.D.,M.D. 5 Director, OHRP 6 Education 7 Jeffrey Cohen, Ph.D. 8 Director, Division of Education 9 Assurance 10 George Gasparis, Acting Director 11 Division of Assurances and Quality 12 Improvement 13 14 15 16 17 18 19 20 21 22 5 1 A G E N D A - (Continued) 2 3 1:30-3:30 OHRP 4 Compliance 5 Kristina Borror, Ph.D. 6 Division of Compliance 7 International 8 Melody Lin, Ph.D., Deputy Director 9 and Director, Office of Policy and 10 Planning, and Special Projects 11 Policy 12 Irene Stith-Coleman, Ph.D. 13 Director, Office of Policy, and 14 Planning, and Special Projects 15 16 3:30-3:45 Break 17 18 3:45-4:30 Update and Discussion: Third Parties: 19 Research Subjects? 20 Mary Kay Pelias, J.D., Ph.D. 21 Chairperson, Working Group 22 6 1 4:30-4:45 Closing Comments/Adjourn 2 Mary Faith Marshall, Ph.D. 3 4 ROSTER OF MEMBERS 5 6 MARY FAITH MARSHALL, Ph.D., Chairperson, Director 7 of Program in Bioethics, University of Kansas 8 Medical Center 9 10 GREG KOSKI, Executive Secretary, Ph.D., M.D., 11 Director, Office of Human Research Protections, 12 Office of Public Health and Science, OS 13 14 MARK BARNES, J.D., LL.M., Partner, Proskauer Rose 15 LLP 16 17 MS. MARGARET BORWHAT, President, Women's Cancer 18 Advocacy Network 19 20 SANFORD CHODOSH, M.D. 21 22 7 1 ELLIOT N. DORFF, Ph.D., Rector, Distinguished 2 Professor of Philosophy, University of Judaism 3 4 ALAN R. FLEISCHMAN, M.D., Senior Vice President, 5 The New York Academy of Medicine 6 7 JENNIE R. JOE, Ph.D., M.Ph.H., R.N. 8 Professor, Family and Community Medicine 9 Director, Native American Research and Training 10 Center, University of Arizona 11 12 SUSAN Z. KORNETSKY, M.P.H., C.I.P., Director, 13 Clinical Research Compliance, Department of 14 Clinical Investigation 15 16 FELICE J. LEVINE, Ph.D., Executive Officer, 17 American Sociological Association 18 19 ROBERT LEVINE, M.D., Professor of Medicine, Yale 20 University School of Medicine 21 22 8 1 ABBEY S. MEYERS, President, National Organization 2 for Rare Disorders 3 4 JONATHAN D. MORENO, Ph.D., Emily Davie and Joseph 5 S. Kornfeld Professor of Biomedical Ethics, 6 Director, Center for Biomedical Ethics, University 7 of Virginia Health System 8 9 MARY Z. PELIAS, Ph.D., J.D., Professor, Department 10 of Genetics, Louisiana State University Health 11 Sciences Center 12 13 Roster of Members (Continued) 14 15 ROBERT R. RICH, M.D., Executive Associate Dean of 16 Research, Emory University School of Medicine 17 18 ADIL E. SHAMOO, Ph.D., Professor, Department of 19 Biochemistry and Molecular Biology, University of 20 Maryland School of Medicine 21 22 9 1 JUDITH L. SIEGEL, Ph.D., Vice President, Head U.S. 2 Clinical Operations, Hoffman-La Roche, Inc. 3 4 DENYSE THORNLEY-BROWN, M.D., Assistant Professor, 5 Division of Nephrology, University of Alabama at 6 Birmingham 7 8 KATE-LOUISE GOTTFRIED, J.D., M.S.P.H., Executive 9 Director, National Human Research Protections 10 Advisory Committee 11 12 EX-OFFICIO MEMBERS 13 14 Dr. James Shelton, USAID 15 Dr. Maryann Danello, CPSC 16 Dr. Joseph Spence, USDA 17 Ms. Linda Beth Schilling, USDOC 18 Mr. Tryn Stimart, Alternate 19 CDR Douglas Forcino, DOD 20 Ms. Blanca Rosa Rodriguez, DOED 21 Dr. Susan L. Rose, DOE 22 10 1 Dr. Dixie Snider, DCD, DHHS 2 Dr. David A. Lepay, FDA, DHHS 3 Dr. Belinda Seto, NIH 4 Alan Sandler, D.D.S., NIH 5 Dr. Francis D. Chelsey, Jr., Healthcare Research 6 Dr. Paul Gatons, DHUD 7 Dr. Donald Prosnitz, DOJ 8 Mr. Thomas G. Raslear, DOT 9 E. Donald Sussman, Alternate 10 Dr. John H. Mather, DVA 11 Joan Porter, D.P.A., MPH, Alternate 12 Mr. Roger S. Cortesi, EPA 13 Dr. Richard S. Williams, NASA 14 Dr. Philip Rubin, NSF 15 Mr. Howard L. Bradley, SSA 16 17 18 19 20 21 22 11 1 P R O C E E D I N G S 2 [Time noted: 8:40 a.m.] 3 CHAIRPERSON MARSHALL: Good morning and 4 welcome all committee members, our ex-officio 5 members, our visitors and public members. I am 6 Mary Faith Marshall and I chair the National Human 7 Research Protections Advisory Committee. Many of 8 you are friends and acquaintances. 9 Let me just say to those of you who have 10 not attended one of our meetings before that, we 11 will allow during the course of the day and the 12 course of our meeting ample time for any and for 13 all to speak. 14 Our agenda to set up differently perhaps 15 than another meetings you may have attended in the 16 past, other FACA meetings, in that we allow the 17 same amount of time for committee members, ex- 18 officio members and members of public to speak 19 about the issues at hand. 20 I would like to welcome all of you and it 21 is a special honor and privilege to welcome Dr. 22 Arthur Lawrence who is the Acting Principal Deputy 12 1 Assistant Secretary for Health at the Department of 2 Health and Human Services and human subject 3 protections. 4 Those of us who sit on the Committee know 5 him well. He has appointed each of us to this 6 Committee and has been instrumental in the founding 7 of the National Human Research Protections Advisory 8 Committee and the Office for Human Research 9 Protections and has been a stalwart -- to me as the 10 Chair of the Committee and to Kate as the Executive 11 Director to Greg Koski as the Executive Secretary 12 of the Committee and also as the Director of the 13 Office for Human Research Protections. 14 Art, we thank you so much for all of your 15 guidance in the past and for your support and we 16 are honored to have you here with us today. 17 [Applause.] 18 DR. LAWRENCE: [Off mic.] I don't need 19 microphone [inaudible] -- will argue -- 20 It is a pleasure to be here -- 21 Also the folks who are sitting in the 22 audience because in fact the greater community will 13 1 not benefit from research in advancing human 2 medicine and in human knowledge unless we can 3 assure individuals as they participate in trials 4 that they are protected to the maximum extent. 5 This is very, very much an Exdionian 6 community activity. The folks in the community may 7 not understand it, but when I go to places like my 8 hometown in New Hampshire that probably doesn't 9 have but maybe one trial going on in a small part 10 of the town, I try to explain to them the 11 importance of this sort of -- extend my thanks to 12 the Committee because they are taking on such tough 13 issues. 14 These are issues that need to be discussed 15 the public which need to be discussed at a high 16 level and they need to be discussed in the public 17 interest. And they are tough. 18 These are not easy issues. I once had 19 somebody tell me that a certain advisory committee 20 which was set up in the late '80s was going to deal 21 with all the tough issues up front, but I have yet 22 to see that committee deal with any issues that 14 1 wasn't tough. So this takes an awful lot of 2 people's time, it takes people away from their 3 children and their family. And I would extend on a 4 personal note saying that I give personal thanks 5 because both my daughter and I at one time or 6 another have been human subjects. 7 I appreciate what this committee does and 8 I appreciate the advice that it is giving us and 9 the public health service and the department and I 10 look forward to a bright future for the committee 11 as it moves forward through human subjects 12 protection in the United States. 13 So let me now just slink away and go argue 14 for some money. Once again thank you very much and 15 the best to you all. 16 [Applause.] 17 CHAIRMAN MARSHALL: We apologize for the 18 feedback problem. I think they're trying to work 19 on it and I know it is irritating. So I hope that 20 it would disappear soon. 21 We do have a very full agenda for the next 22 two days. We have been working hard and we have a 15 1 lot work to do. So I am going to forego my usual 2 housekeeping remarks unless something comes up 3 within the context except to remind all of us that 4 we should be thoughtful in terms of what we have to 5 say, we should be stewards of our time and others' 6 time and please do not hold back in terms of things 7 that are important that need to be put on the table 8 and that need to be said relative to the protection 9 of human research subjects and conflicts of 10 interest. 11 I'm now very glad to introduce to you Dr. 12 Michael Wood. Dr. Wood is the president and CEO of 13 the Mayo Foundation. He is going to speak to us 14 this morning on the perilous intersection of 15 protecting human research subjects and conflicts of 16 interest. And it will be, I think, a beautiful 17 segue into the work that we have been doing on 18 financial relationships. 19 Welcome, Dr. Wood. 20 [APPLAUSE.] 21 DR. WOOD: Thank you, Mary Faith. 22 Good morning everyone. I think we will be 16 1 able to get started here right away as soon as we 2 get our visuals all set up. It is always a little 3 bit of the risk with PowerPoint. 4 You can all gather around the computer 5 here and we will move on. 6 Here we go, relief is on the way. 7 CHAIRPERSON MARSHALL: These multi- 8 talented OHR people. It's a real teacher. 9 DR. WOOD: Well, again, good morning. I 10 hope everyone got here all right with the rain and 11 all that. It seems like a pleasant summer in 12 Washington. I also appreciate the opportunity to 13 be here and spend a few minutes with you talking 14 about what I think is a very important subject for 15 the medical profession today. 16 Medical discoveries and exciting new 17 advancements are progressing very rapidly; if one 18 just considers between the bronze age and the 19 1900s, man's life expectancy increased 27 years. 20 And then between 1900 and 2000 yet another 27 years 21 was an added to the average life expectancy. 22 Many are expecting predicting frequent, 17 1 perhaps routine, life spans beyond age 100 in the 2 next generation or two with functionality of middle 3 age developed by today's standards. This is not 4 particularly good news for pension benefits 5 managers. But it might be just what the doctor 6 ordered for our children are grandchildren. 7 In the last few years especially, advances 8 in information technology and enacting of the human 9 genome have opened a portal for advancement in 10 medicine unrivaled since the discovery of 11 penicillin and this comparison may in fact be an 12 underestimation. 13 All of these advances are creating 14 unprecedented opportunities for scientists and 15 inventors who are often funded by public monies. 16 They can become highly successful entrepreneurs who 17 have loyalties, licensings of intellectual property 18 and actually been founders in start-up companies. 19 Well, why is this a relatively new subject 20 of discussion? Some might argue that is not a new 21 subject and to support this position let us 22 consider the position of Dr. Benjamin Waterhouse, 18 1 one of three, full-time professors at Harvard 2 Medical School in 1799. 3 Dr. Waterhouse learned of generous 4 observations about the efficacy of cowpox 5 vaccinations for smallpox through generous written 6 reports to the royal college. Waterhouse proposed 7 to test the vaccine in Boston by a clinical study 8 which included his own children and 19 others who 9 were then exposed to smallpox. 10 If successful he proposed to develop a 11 monopoly to inoculate New England children for a 12 fee. His clinical trial was successful. None of 13 the children, and most especially his own, 14 contracted smallpox. 15 I cannot tell you what his wife had to say 16 about all of this, but his two colleagues at 17 Harvard Medical School perceived his proposal as 18 most reckless and self-serving. As a result, Dr. 19 Waterhouse was expelled from Harvard in 1812 20 despite President Thomas Jefferson dubbing 21 Waterhouse as the founding father of vaccination in 22 this country. 19 1 And to my knowledge, his vaccine monopoly 2 never materialized been no fees of any lasting 3 substance derived to him. 4 Beyond this example, perhaps one of the 5 major reasons why entrepreneurs in medicine was not 6 a frequent or comfortable mix. Prior to World War 7 II most, if not all, medical research funding came 8 from internal forces. Universities through 9 tuitions, some private philanthropic foundations, 10 and the practice revenues from academic medical 11 institutions. 12 Moreover, societal expectations for 13 academics and medical researchers were different. 14 A strong assumption of altruistic motives. 15 Following World War II, building for the 16 military infrastructure, public funding became 17 accepted and perhaps even expected by society as a 18 source of funding for medical research to benefit 19 society. 20 Thus, the National Institutes of Health 21 became ever more important as a catalyst for 22 medical research and was supplemented by 20 1 increasingly relevant participation of private 2 foundations. 3 If one considers the response by Jonas 4 Salk when asked, "who owns the right to his polio 5 vaccine discovery?" His answer was, "well, the 6 people I would say." There is no problem -- this 7 was clear recognition that public funding supported 8 his research. 9 By the 1970s, the ability of tax payers 10 and philanthropic organizations to keep up with the 11 appetite for research and the rapid pace of 12 discovery brought on by Sputnik and the space race 13 was stretched to the limit. At this time revenues 14 from patient care began a downwards trajectory and 15 American competitiveness was being challenged by 16 international manufacturers. 17 In the 1960s and 1970s, there was much 18 study surrounding federal patent policy. There 19 seemed to be a lack of success by the federal 20 government in promoting the adoption of new 21 technology by industry. 22 For many reasons there was very limited 21 1 flow of government funded inventions to the private 2 sector. In 1980, the federal government held title 3 to about 28,000 patents. Fewer than 5 percent were 4 licensed to industry for development of commercial 5 products. 6 In 1980, there were approximately only 25 7 to 30 universities actively engaged in the 8 patenting and licensing of inventions. 9 At least in part, this led to the passage 10 of the Bayh-Dole Act in 1980 which was an overt 11 effort to stimulate translation of American 12 scientific discovery to successful commercial 13 activities. 14 In a nutshell, the Bayh-Dole Act gave a 15 grantee and his or her contractor organization, 16 perhaps, for example, a university or a hospital 17 title to inventions resulting from federal research 18 funding. With that title came the happy prospect 19 of sharing in any royalties resulting from 20 patenting the invention. And, indeed, it appears 21 that the Bayh-Dole Act has been quite effective in 22 accomplishing its intended purpose. 22 1 Academic institutions were granted more 2 than 8,000 U.S. patents between 1993 and 1997. 3 More than 2,200 companies had been formed since 4 1980 based on the licensing of an invention from an 5 academic institution. 6 Approximately $30 billion in annual 7 economic activity supporting 250,000 jobs can be 8 attributed to the commercialization of new 9 technologies from academic institutions. There are 10 more than 1,000 products currently on the market 11 based on university licensed discoveries. It is 12 estimated that 70 percent of the active licenses 13 are in the life sciences, yielding products and 14 processes that diagnose disease, reduce pain and 15 suffering, and save lives. 16 The number of university-generated patents 17 has increased from approximately 250 per year prior 18 to the Bayh-Dole Act to more than 4,800 and more 19 than 3,000 licenses in 1998. 20 Along with this, since 1980, industry 21 support for medical research has greatly increased. 22 And has in many disciplines taken over as a 23 1 dominant funding for clinical research trials. If 2 one reduces this to hard dollars, in 1999, clinical 3 research funding from industries totaled $9 4 billion. While that from government was about half 5 of this or 5 billion. At this is not because of a 6 shrinking government support. 7 Indeed, since 1995, the NIH budget has 8 gone up 57 percent through generous taxpayer 9 support and by 2003 is projected to double from its 10 1995 level to $27 billion. 11 As far his clinical drug trials, industry 12 provides an estimated 70 percent of funding. One 13 might say, so what is the problem with industry 14 support? Isn't all the money green? It certainly 15 is not an unreasonable question to raise and in the 16 same vein some logical questions come forth from 17 our commercial partners in this somewhat 18 tempestuous married. 19 For example, if a commercial firm should 20 fund a piece of research, is it not reasonable to 21 expect a return on investment? What control should 22 a company have on the research? Should the company 24 1 have the right to suppress or embargo publication, 2 or unexpected, or worse yet, adversarial results, 3 if they funded it? And if the results are indeed 4 promising, and particularly if they may have the 5 major impact on public health, does a commercial 6 firm, as the funding company, have exclusive rights 7 to the intellectual property? 8 And should researchers funded by a company 9 be expected to endorse the company's products 10 either directly or indirectly? 11 All of this leads us to another question 12 and that is, is entrepreneuralism in medicine 13 really an issue that can in any way harm society or 14 the public at large? 15 One way to get an answer to this question 16 is to observe what makes the front page of 17 newspapers. The Wall Street Journal, January 30th 18 of this year, in one front-page header, "Adroit 19 Scientists Aid Biotech Company With Taxpayer 20 Money." This article cited examples of multiple 21 NIH grant awardees owning a substantial stake in a 22 commercial firm which owned exclusive rights to all 25 1 discovery. Often these commercial firms were in 2 the same facility as the research laboratory. And 3 a few months ago the front page of the USA Today, 4 February 26, '01, both physician and university 5 stand to gain without informed consent. 6 Another fairly recent example that caught 7 the attention of the press, Sandoz Pharmaceuticals 8 now in Novartis signed an agreement with a very 9 well-known American medical research institute the 10 right $300 million in funding in return for the 11 institute giving the company first option to 12 license the institute's biomedical research, 13 including that funded by public monies from the 14 NIH. 15 Ultimately, because of public outcry, and 16 NIH objections, the Institute was forced to 17 scaleback, but not terminate, the agreement. 18 Are there, in fact, some examples of 19 problems or improprieties that have resulted from 20 scientific misconduct whether related to 21 entrepreneuralism or not? There are. Just to name 22 a few: the Tuskegee Syphilis Study, an example of 26 1 scientific misconduct, not entrepreneurial 2 misconduct. It started in 1932, half of a group of 3 men with known syphilis were treated with 4 penicillin and half were not. Neither with 5 informed consent. By 1947 the efficacy of 6 penicillin for treatment of syphilis was well 7 confirmed and was indeed the standard treatment. 8 Despite this, the natural history of 9 untreated syphilis, and 399 people was kept under 10 study without treatment until 1972 when the study 11 was exposed at terminated. At no time were the 12 participants informed of their treatment options or 13 even whether they were being treated. 14 Another the Willowbrook Home Study; this 15 study involved in known exposure of mentally 16 retarded children in a New York institution to 17 hepatitis virus to test the efficacy of a newly 18 developed hepatitis vaccine. Patients and parents 19 were neither informed of the study nor offered the 20 opportunity to decline participation. 21 There also is objective evidence that 22 financial incentives can influence medical 27 1 judgment. A study by Schren and Landafield [ph] 2 suggested that physicians who requested that 3 specific drugs be added to the hospital formulary 4 were more than ten times as likely as their 5 colleagues to have received financial support from 6 the pharmaceutical manufacturers. 7 Votenheimer [ph] reported that industry- 8 supported drug trials are more likely to favor a 9 study drug over conventional therapy than is the 10 case for nonindustry-supported trials. Quotron and 11 Barrel, in separate studies, showed that when a 12 scientist has a financial interest or funding by a 13 company related to his or her research activity, 14 the resulting research is lower in quality and more 15 likely to favor the sponsor's product. 16 So what are the issues at hand? Is it 17 simply a matter that the insulation between medical 18 discovery commercialization has grown thin? Or has 19 this thick asbestos firewall disappeared between 20 academic science for the sake of science and the 21 opportunity for individuals to achieve personal 22 wealth to act as commercialization of their 28 1 intellectual productivity. And most important how 2 can public trust in the medical profession be 3 sustained or in some cases restored? 4 Without appropriate policies and 5 procedures, according to Dr. Kathryn DeAngeles, JMA 6 editor, the academic institutions where most 7 clinical research is based, and their faculty 8 members who perform the research, are in grave 9 danger of losing the support and respect of the 10 public. Without this support and respect, trust in 11 new medical discoveries and their applications will 12 not be forthcoming. Without trust medical research 13 is doomed. 14 And the trust we are talking about is not 15 only from patients, but also from regulatory 16 agencies, legislative bodies, academic partners, 17 and research sponsors. 18 To ensure this trust three significant 19 issues are receiving attention in the medical 20 scientific community. The presence or absence of 21 conflict, either conflict of commitment or conflict 22 of interest, the ethical mandate of full 29 1 disclosure, and the importance of informed consent 2 for all human studies. 3 I would like to comment on all three of 4 these topics and how these three topics represent 5 the minimum standards for contemporary ethical, 6 conduct in medical research. Let us focus first of 7 all on conflict of interest in science. Few topics 8 may evoke more subjectivity in interpretation but 9 most interpretations challenge the notion of 10 objectivity in pure science. 11 Conflicts may be individual in context, 12 that related to personal and individual advantage; 13 or institutional when they favor the objective of a 14 group. 15 One might encounter the institutional 16 conflicts in instances of equity ownership in a 17 biotech company by a university hospital or 18 company. This issue has been in the news in recent 19 months in regards to a very well-known and 20 respected university campus center involving the 21 institution as a whole and a number of their 22 investigators. 30 1 And as recently as this month the editors 2 of the Journal of the American Medical Association 3 announced a more specific and more stringent policy 4 for reporting offers, financial conflicts of 5 interest, and a new policy reporting relationships 6 between investigators and research sponsors. 7 There is not universal agreement about the 8 definition of "conflict of interest." In most 9 cases it denotes a situation rather than an act or 10 behavior that is a potential problem rather than a 11 done deed. 12 Jordan Cohen, President of the American 13 Medical Association of Medical Colleges, defined 14 "conflict of interest" as follows: a conflict of 15 interest exists whenever an individual or an 16 institution has a primary allegiance that requires 17 certain actions and simultaneously has a secondary 18 interest that could abrogate the primary allegiance 19 and the sufficient attempting to raise a reasonable 20 possibility that it might actually do so. 21 In other words, a situation where one's 22 judgment about what is best for an individual 31 1 patient could be hindered. 2 Conflicts may be real or perceived and may 3 be financial or non-financial. Most people and the 4 public tend to think in terms of financial 5 conflicts of interest because it is quantifiable 6 and it is easy for most people to relate to. 7 Conflicts might also be in appearance 8 only; and these too can be quite serious. In fact, 9 in most cases it is the appearance of conflict that 10 may inflict a devastating blow on the medical 11 profession in terms of public trust. A recent 12 example of this might be illustrated by the highly 13 publicized case of Jesse Gelsinker, [ph] the 18- 14 year-old boy who died in 1999 from complications of 15 an experimental gene therapy program at one of this 16 country's leading medical schools. 17 It was only later that his family and the 18 public learned that the doctor running the clinical 19 trial had in equity interest in the biotech company 20 sponsoring the trial. Conflicts in some cases can 21 be avoided but in some cases this is not possible. 22 Dr. David Korn, Senior Vice President of 32 1 the Association of American Medical Colleges has 2 written, "that conflicts of interest are ubiquitous 3 and inevitable in academic life." Indeed, in all 4 professional life. The challenge for academic 5 medicine is not to eradicate them, but to recognize 6 and manage them sensibly and effectively. Thus, 7 mitigation, rather than avoidance, is often what is 8 required when dealing with conflicts. 9 One of the ways to mitigate conflict, and 10 in many instances to minimize the development of 11 conflicts, is to require full disclosure of any 12 secondary interest from anyone in a position of 13 public or institutional trust. This, in fact, is a 14 condition of employment for 55 percent of the major 15 biomedical research institutions in this country as 16 of 1999 and is increasingly regarded as a minimum 17 requirement to safeguard ethical behavior. 18 Disclosure should be to colleagues, 19 students, and certainly patients, and should be 20 included in consent forms, publications, and 21 presentations regarding specific research. 22 Disclosure should also address both individual and 33 1 institutional conflicts. 2 In most cases, disclosure is required of 3 any relations or transactions that involve money, 4 tangibles of value, for example, gifts, equity in a 5 company, even if of little current value, support 6 for researcher education, and other perks; for 7 example, tickets for sporting events, receptions, 8 et cetera. 9 At times, depending upon the human risk 10 level, disclosure alone is insufficient, and other 11 measures such as subject-by-subject external review 12 or actual divestiture of interest is more 13 appropriate. 14 The final issue that I would like to 15 discuss that is increasingly challenging public 16 trust in medical research is the adequacy of 17 informed consent for his human studies. This is 18 something that affects all of us. It acknowledges 19 our society's respect for an individual's 20 prerogative to opt in or to opt out of unproven 21 treatments. 22 Let me briefly review some of the history 34 1 leading up to our present informed consent policies 2 in this country. In the 1960s the U.S. Food, Drug, 3 and Cosmetic Act amendment was passed which 4 mandated that people must consent to participate in 5 experimental therapy. This was prompted by some 6 anecdotal but egregious examples of the use of 7 experimental and unproven therapies on people 8 without adequately informing them of the context. 9 Probably the most notable among these is the high 10 incidence of upper limb abnormalities in babies of 11 pregnant women taking thalidomide. 12 In 1967, the FDA policy clarified that 13 informed consent for clinical studies must be in 14 writing. In the 1970s, the National Commission for 15 the Protection of Human Subjects of Biomedical and 16 Behavioral Research was established. In part, a 17 direct result of the Tuskegee study previously 18 discussed. The national commission recommended 19 that all institutions engaged in biomedical 20 research establish an institutional review board to 21 review all studies involving human subjects. 22 This was followed in 1972 by the 35 1 establishment of the Office of Protection from 2 Research Risks within NIH to monitor the safety of 3 all clinical studies funded by NIH. And just in 4 June of 2000, the Office of Human Research 5 Protections was established as part of HHS, which, 6 of course, is related to why we're here this 7 morning. 8 Has the mandate for institutional review 9 boards and the establishment of various offices 10 within our regulatory agencies taken care of the 11 problem? Let me again cite a recent newspaper 12 article, USA Today, February 26, 2001. "Great 13 medical advances have been made but there also have 14 been costs, increasing scientific misconduct and 15 patient debts and fully informing human volunteers 16 of health risks is being eroded in a mad dash for 17 money and fame." And just two weeks ago, the 18 adequacy of informed consent was questioned in the 19 press relative to the Hexancarnonium induced asthma 20 study that was associated with the death of a study 21 participant nearby. This ultimately led to the 22 temporary suspension of all federal funding for 36 1 human research at one of the most prestigious 2 medical universities in this country effective July 3 19th. 4 From the regulatory perspective the 5 mainstay of human studies protection at the present 6 time must be the Institutional Review Board because 7 it is the infrastructure in place that can best 8 accomplish the tests. There are about 6,000 IRB's 9 in the U.S.; virtually all medical research 10 institutions receiving federal funding must have 11 one or a relationship with one. 12 The overwhelming majority of these review 13 boards do an excellent job of protecting patients, 14 and these fall under the purview of the Office for 15 Human Research Protections. However, occasionally, 16 the decisions and reach of IRB's can fall into a 17 gray zone which in many cases leads to the dilemma 18 of unproven research versus offering the latest 19 potential breakthroughs in clinical care. 20 In these types of cases it is not an 21 institutional review board but the treating 22 physician whose level of honesty and integrity will 37 1 determine if informed consent is required, 2 appropriate, and fairly presented. 3 Let me conclude this subject by a quote 4 from a bioethicist, Dr. Arthur Kaplan of the 5 University of Pennsylvania. "Informed consent is 6 the absolute bedrock of the protection systems." 7 In summary, we have touched on some of the 8 issues and challenges that entrepreneurial 9 opportunities are presenting to the medical 10 profession. The balance between professionalism 11 and blatant capitalism may be hard to titrate, 12 especially in those fields of great biotechnology 13 interests. 14 There are three safeguards that are 15 presently available and these should be compromised 16 only with the great caution or concern. They 17 include the avoidance or negation of conflicts, the 18 requirement for full disclosure of secondary 19 interests, and the uncompromising use of informed 20 consent for all investigational treatments 21 presented in an objective and fair manner. These 22 are emerging as the minimum standards of ethical 38 1 conduct in the medical profession. 2 May I finish with a quote from EMJ mail 3 from 1921. "Commercialism in medicine never leads 4 to true satisfaction and maintaining our self- 5 respect is more precious than gold." 6 At Mayo Clinic, our primary value 7 statement is captured in seven words, "the needs of 8 the patients come first." If that is the ultimate 9 goal for all involved, conflicts of related 10 professional ethical issues can be effectively 11 managed and the most appropriate choice between 12 negation or elimination of conflict will likely 13 become more obvious. 14 Thank you very much and I will be happy to 15 answer any questions at this time. 16 [Applause.] 17 CHAIRPERSON MARSHALL: We do, I believe, 18 have ample time. So what I would like to do is to 19 follow our pattern and give the committee some time 20 for questioning and our ex-officio members and then 21 our public members. 22 And first I would like to recognize Dr. 39 1 Fleischman. 2 DR. FLEISCHMAN: Dr. Wood, thank you very 3 much for your presentation. In a few minutes we're 4 going to review an interim guidance recommendation 5 and I wonder if you have had an opportunity to 6 review that and if you have any wisdom about -- 7 comments about it? 8 DR. WOOD: Alan, I have not have the 9 opportunity review that, but if you want to pick 10 out any particular hot button items and ask for an 11 off-the-cuff opinion, I would be happy to do so. 12 CHAIRPERSON MARSHALL: Jonathan. 13 DR. MORENO: Thank you for that, that was 14 an excellent summary. Regarding your three minimum 15 standard of ethical conduct, I do not think anybody 16 would disagree with those standards, but putting 17 them in context of the two incidents that you 18 mentioned, namely the death at Penn and the recent 19 death at Hopkins, it's not clear to me that any of 20 them actually speak to what appears to have 21 happened in each those cases, let's say what 22 appears to have happened in the Gelsinger death 40 1 seems to have something to do with inadequate 2 protection and evaluation of the subject from a 3 medical point of view. And in the case of the 4 Hopkins death, there are allegations that there was 5 poor preparation on the part of the investigator 6 with respect to the effect on human subjects of the 7 drug that was being used in that physiologic study; 8 whether that is the case or not, I do not know, but 9 that is what is being said at least. 10 So what the standards, which are the same 11 kind of standards that I have urged in my own 12 talks, are clearly very important with respect to 13 sustaining public confidence in the system. Does 14 it seem to you that there are some perhaps with 15 respect to these two cases anyway there are some 16 other problems that might occur that are matters of 17 human error that are much harder for us to identify 18 in advance. 19 DR. WOOD: Jonathan, I would certainly 20 agree with the final statement that you made. I 21 think the area that is most within our control at 22 this time really backs up to the issue of public 41 1 trust and I think that although all of us in 2 dealing with the active treatment of patients 3 recognize that the potential for pitfalls are 4 significant in terms of not being able to control 5 the response in biology, but certainly the 6 standards by which we move forward and offer 7 treatment to our patients. It is something that I 8 think in recent years has become recognized as more 9 and more of an issue. And it is likely that many 10 of these things will be listed for a long time, 11 going back to Dr. Waterhouse. 12 However, with the awareness of the issues 13 at the present time, it has just ramped up the 14 standards by which we all must behave and I think 15 it is clear that we do not do this, and we do not 16 step up to it, it is going to have devastating 17 effects on how we interrelate with our patients and 18 the public. 19 DR. DORFF: Are you aware of any other 20 country that has done this in a way that you think 21 is better than the way we're doing it? 22 DR. WOOD: I think if one turns over all 42 1 the rocks that were -- I would not say that we are 2 any worse off than any other country. Indeed, I 3 think if one really looks into most of our peer 4 countries, if you will, one might say, aren't we 5 setting the standards even higher than several? 6 And I think that unquestionably is going 7 to be a worldwide issue, but I think this country 8 has to be the pacesetter in terms of that. The 9 rest of the world looks at us, I think, for these 10 types of protections. And unfortunately the 11 converse of that is that the intellectual linkage 12 that is occurring in this country because of more 13 liberal standards, if you will, I would not say we 14 are any worse off than anyone else, but I do think 15 this country has to be held to a little higher 16 standard maybe than the rest of the world because 17 we're looked at for that purpose. 18 CHAIRPERSON MARSHALL: Let me just 19 interject for a moment before I recognize Susan. 20 For those of you who are standing in the back, 21 there are multiple seats on the front row. So if 22 you would like to, please come up front. 43 1 DR. KORNETSKY: Picking up from Alan's 2 comment that we are now trying to put together a 3 practical type of guidance for institutions to 4 think about this and realizing that there are some 5 institutions that have very sophisticated systems 6 about thinking about conflicts of interest and 7 others that don't, from your experience at Mayo, 8 what works of what does not work? 9 DR. WOOD: Well, probably the most 10 powerful impact of all institutionally is the peer 11 pressure to do this. And I think as far as the 12 actual mechanic stuff, to get to that peer pressure 13 to be the individual setting the high standards, I 14 think the most significant advance that we have 15 done in the last several years in this regard is 16 actually set up a conflict of interest 17 subcommittee. And for many, many years we had a 18 body known as the Medical Industrial Relations 19 Committee that has looked at these source of 20 issues. But setting up a targeted conflict of 21 interest subcommittee I think very much puts the 22 issue right in everyone's face so they can 44 1 understand where conflicts exist. 2 We started out with this totally as an 3 internal body and I know many other universities 4 have done this, but I think even to take it to the 5 standard that IRBs are at this point, that is 6 inviting public members -- in fact a committee will 7 probably the be the next evolution that we will be 8 undertaking. But I think this is something that is 9 well within the control of any university without 10 establishing a burdensome bureaucracy, if you will, 11 -- 12 DR. KORNETSKY: Just a quick follow-up, 13 your institutional relationship, you are talking a 14 lot about how this impact IRBs and where 15 responsibility lies, how does that committee in 16 interact with the IRB? 17 DR. WOOD: Well, it is an independent 18 committee of the IRB. And for a couple practical 19 reasons, I'm not even talk about looking for a huge 20 amount of detail, but most academic institutions 21 will have a certain amount of turnover on their IRB 22 and it is kind of an obligation of faculty members, 45 1 and typically, at least, I find it is not 2 particularly embraced or welcomed as a diversion to 3 keep in the UK say have to begin video three nights 4 before the meetings every week. But I think what 5 comes a conflict of interest there are some issues 6 here that really need some tenure, if you will, and 7 experience in this. I think one of the reasons 8 that we are -- one of the bases and fundamentals at 9 least in our own subcommittee is to have a group of 10 people who actually have had for some time to get a 11 chance to really become wise in their judgments 12 rather than just knowledgeable. 13 CHAIRPERSON MARSHALL: I had Greg Koski 14 and then Abbey. 15 DR. KOSKI: Dr. Wood, since the draft 16 document that is our interim guidance draft was put 17 out, we have heard a lot of discussion around the 18 fact that it breaks new ground in terms of 19 addressing institutional conflicts of interest and 20 people repeatedly say, this is a complex area. 21 Since you are here before us as someone who leads 22 one of these big institutions, what is it that is 46 1 so new about institutional conflicts of interest, 2 that concept, and what do you see as the sort of 3 major challenges that need to be addressed in terms 4 of, you know -- 5 DR. WOOD: Greg, I think one of the major 6 issues, at least one that we have had some direct 7 experience with, is the fact that you can have 8 institutional conflicts coexist without individuals 9 really recognizing it and the potentiality of 10 influencing their judgments. One of the practical 11 issues that we have been dealing with is how do we 12 ensure that everybody who is a position to exercise 13 choice over something actually recognizes the 14 institutions possible involvement. 15 I think the other thing is that in the 16 next decade it is very likely that this becomes 17 more and more of an issue and I know that you kind 18 of joined us last March when we had a day of 19 discussion in this, primarily because I do not know 20 of any academic institutions that is not trying to 21 strongly consider what are the acceptable mutual 22 opportunities between sources of funding and 47 1 creating partnerships with commercial firms to help 2 have them meet their academic mission. And at this 3 point in time, I think just inadequate thought has 4 been put into how are these actually going to play 5 out. 6 And, unfortunately, there are enough 7 anecdotes out there about how institutions have 8 become enamored with the source of income and the 9 potentiality for them to influence their judgment 10 that the time has clearly come, may be just a few 11 years late, but better late than never. 12 So I would like to say on behalf of one of 13 those academic institutions that we very much 14 appreciate the work of this committee and your 15 agents. 16 CHAIRPERSON MARSHALL: Abbey. 17 MS. MEYERS: One of the issues that we are 18 wrestling with is whether informed consent 19 documents should specifically state the dollar 20 amount -- that an investigator or an institution 21 should have, or whether there should just be a 22 generalized statement saying the conflict of 48 1 interest committee has looked into. At Mayo, in 2 that informed consent document, does it say -- 3 DR. WOOD: -- informed consent we do not 4 require the dollar amount between the investigator 5 and the study participants. However, we do require 6 the dollar amount to be revealed through the 7 conflict of interest subcommittee. I think we felt 8 that was a fairly reasonable compromise since the 9 ability of an individual to get focused on the 10 dollar amount as opposed to the risks involved, in 11 fact there is a downside as well as a plus side, 12 however, the conflict of interest subcommittee I 13 think they are a body that is used to seeing these 14 sort of things and are used to weighing that and 15 understanding, you know, when is that consistent 16 with, if you will, "the market" for this sort of 17 intellectual property versus not? 18 [Sound outage.] 19 DR. WOOD: One that is put in language 20 that the participants can understand, but we have 21 not gone to the level of detail that you just asked 22 at that level, rather up the line at the 49 1 institutional review level. 2 CHAIRPERSON MARSHALL: I'm going to take 3 two more questions from committee members. I have 4 Sandy and then we will open things up. 5 DR. CHODOSH: Dr. Wood, your excellent 6 presentation really seem to stress the relationship 7 of academia and industry, and did make one 8 statement which I think might be in question and 9 that is pharmaceutical research, I think that there 10 was more pharmaceutical research now outside of 11 academia than within academia and I wonder what 12 your thoughts are about how do we approach those 13 problems because many more human subjects are being 14 involved outside of academia and it seems there's 15 no control over it and industry has all the 16 control. 17 DR. WOOD: Well, I think you point out 18 another problem that's right there and I agree, 19 most of our efforts have been in dealing with how 20 an institution of a certain size can actually set 21 its own level of standards, and I do not have the 22 answer to that. But I do think that academia needs 50 1 to lead the way. I think they need to be active 2 participants in setting the standards and actually 3 adhering to the standards themselves. Because I 4 think the failure to do so will open the 5 floodgates, if you will, for those more diffuse 6 areas and particularly for the large clinical 7 research organizations. 8 I think if we are successful in getting 9 strong compliance with our academic community in 10 this regard, the CROs will certainly feel a 11 significantly greater degree of pressure to follow 12 suit. 13 CHAIRPERSON MARSHALL: And I hate to ask 14 you use a microphone, but we are going to 15 reposition them during the break so they are easier 16 to access and maneuver towards. 17 AUDIENCE PARTICIPANT: Dr. Wood, I enjoyed 18 her presentation very much. I was curious, as a 19 follow-up to Abbey Meyers' question, you do not 20 really say very much in your document other than 21 there is a tangible reward that may accrue to the 22 physician or the institution, how many people 51 1 actually opt into such as study group -- I'm not 2 going there. -- it seems so general that I would 3 be surprised if anybody dropped out with the kind 4 of verbiage you mentioned; do they? Would you join 5 a study because of that? 6 DR. WOOD: I would probably have to give 7 you a very off-the-cuff type of response to that 8 that I would admit to you that relatively few 9 people that I am aware of ever opt out, based on 10 that. I think that probably the bigger issue, at 11 least for us, is how an investigator is viewed by 12 their peers as they are moving forward here. It is 13 certainly my impression that that is the biggest 14 area of where the standards really are adhered to, 15 is at the peer interaction. But I really cannot 16 give you any information about the actual incidence 17 of people either not agreeing to participate; 18 certainly those do exist. 19 AUDIENCE PARTICIPANT: Well, you know, 20 this thing is true in our institute really, at the 21 Child Health Institute at NIH, almost no child ever 22 refuses to join the study no matter what they're 52 1 told. Because if they do, their brothers go home 2 and hit them and the next day they come back and 3 enter the study. 4 Another question I had, the thing you 5 ended with, was about the Mayo Clinic and you said 6 that the patient's needs are primary; that is our 7 primary goal. But who in the world determines the 8 patient's needs? Is it the patient? Is it the 9 family? Is it the doctor? Or some researcher that 10 happens to be passing by the bedside and say, you 11 need adfixinam, there's no question about it and if 12 you don't get and join the study, you are in danger 13 of clotting to death. 14 [Laughter.] 15 AUDIENCE PARTICIPANT: So, the point is, 16 who determines the patient's needs? If it is so 17 important, you can't just get away with that 18 without deciding where these needs are and who does 19 it. 20 DR. WOOD: Well, I think that is the key 21 issue. I think the patient's needs really have to 22 be done in concert with the patient, the family, 53 1 and the physician. It certainly can be subjective, 2 at least in our institution, it is considered 3 absolutely mandatory that the patient be part of 4 determining what their needs are. And the needs of 5 one patient may a turn out to be a little different 6 than the needs of the next patient in the door. 7 AUDIENCE PARTICIPANT: Absolutely. Thank 8 you very much. 9 CHAIRPERSON MARSHALL: Any other questions 10 from our ex-officio members or from members of the 11 public? Please, go to a microphone. 12 MR. SUSKO: Hi, my name is Mike Susko, and 13 I am president of a nonprofit, CRCR, Citizens for 14 Responsible Care in Research, and the question I 15 have is, have you encouraged any studies to see how 16 conflicts of interest actually distort the 17 scientific data. I think there have been some 18 studies done where the researchers who have those 19 interests tend to find, you know, more favorable 20 results. I am just wondering about the actual -- 21 of what is trying to be done. 22 DR. WOOD: I'm not aware at Mayo that any 54 1 specific studies have been done in our institution 2 in regards to that, but I cited about four studies 3 that have been done that have shown the adverse 4 effects of having some equity relationship or 5 potential conflicts in terms of the quality of 6 study. I think it is relatively remarkable that I 7 am aware of almost no study that has not shown some 8 linkage in this regard. I think we can almost take 9 it and fairly well scientifically documented that 10 the existence of a conflict has a much greater 11 chance of influencing results in a negative 12 direction than in a positive direction in a 13 relationship to the objectivity that we are trying 14 to reinforce. 15 MR. SUSKO: So it is there a more 16 permanent solution to perhaps remove the degree of 17 conflict of interest -- 18 DR. WOOD: Well, probably the most 19 permanent solution is actually removal of 20 conflicts. And, as a mentioned, even in our own 21 institution, sometimes we need to do this. But I 22 think in most regards, mitigation is still the area 55 1 where most people are focusing in rather than 2 complete removal. And I think there are ways that 3 the research institutions in this country can do a 4 much better job at mitigation rather then just jump 5 to the alternative of complete removal. 6 I realize that there have been some 7 statements, no conflict, no interest, but I think 8 that is the other extreme of the situation as well. 9 But at the present time, I do think there is a more 10 middle ground that can benefit our patients and the 11 public considerably more than they doing right now. 12 CHAIRPERSON MARSHALL: I will give the 13 last question to Dr. Koski. 14 DR. KOSKI: Thank you, Dr. Marshall. We 15 seem to enter these discussions frequently with a 16 sort of bias if you will that money is the root of 17 all evil. But I heard consistently and as you 18 heard very compelling arguments from industry, from 19 individual entrepreneurs, and so on. In fact the 20 risk to a company, for instance, that is investing 21 in the design of a new product, it is so great that 22 if there's anything that is done wrong that in fact 56 1 there be no greater guarantee that things will be 2 done right and will be not only according to the 3 rules but would never want to harm anyone than 4 having your money tied up. 5 So that in fact money can be, you know, if 6 you are looking at it from the business case, if 7 you invest, you know, multiple millions of dollars 8 in development only to find out that data has been 9 fabricated or individuals have been harmed and so 10 on, you basically, you lose a lot more that way. 11 I was recently at a meeting of the medical 12 technology leadership forum where these issues were 13 discussed at some length and was impressed by the 14 fact that I think there is some validity to that 15 argument and there is another side of this that I 16 have not heard discussed as fully as it might be 17 before this group. And I wondered what your 18 reaction to that might be. 19 DR. WOOD: Greg, I would agree with you. 20 In other words, I think that it just comes back to 21 the Bayh-Dole Act. I think medicine in this 22 country has been seriously propelled forward and 57 1 for the benefit of our patients by the fact that we 2 have opened up a whole level of activity that we 3 may have been at a more indigent without those 4 possible pathways. And I do think it is a mistake 5 to characterize industry as the great savings in 6 this sort of thing. 7 There are many commercial firms that in 8 fact realize that their business strategy has to be 9 based on being absolutely ethically pristine. 10 You can turn back a few layers and you 11 certainly can cite examples where there is another 12 direction. I've heard many of the representatives 13 from FARMA also talk about the valuable role that 14 they are placed in, in terms of educating the 15 public on possible new therapeutic options and 16 things of this nature as well, and there probably 17 is an element of truth to it. But I think for all 18 those reasons it is going to be hard to be way to 19 the right or way to the left on this issue and we 20 need to try to approach it sensibly but bearing in 21 mind that we really need to keep the needs of the 22 patients in front of us. 58 1 MS. MEYERS: Do you ever look at the 2 contracts that some of these investigators have 3 with these companies? For example, there is a 4 paragraph in their that says that the company will 5 have the final say on whether an article should be 6 published if the study comes out negative, for 7 example, or that the company has to review any 8 publication of the journal -- 9 DR. WOOD: We review -- we do not allow -- 10 I'm talking about Mayo -- we do not allow an 11 interaction between any of our staff and a 12 commercial firm in any other format except under a 13 contract. And those contracts are all done by a 14 central body. 15 For example, the point you raised, that we 16 would not sign a contract that requires any 17 stipulations on publishable ability even a certain 18 period of bottling it. I know that on the other 19 side of it I hear from some of our faculty that 20 that is being excessively fastidious about our 21 relationship, but I think we feel it is just one of 22 the standards that we wish to put forward and -- 59 1 MS. MEYERS: The IRB or conflict of 2 interest community review those contracts? 3 DR. WOOD: Well, the committee that I 4 previously mentioned, the Industrial Relations 5 Committee reviews all the contracts and we have an 6 assigned lawyer for those activities. And its only 7 those that have a potential for personal or 8 institutional conflict that backup to the conflict 9 of interest subcommittee. The MEDRIL Committee is 10 the main ship. That is the mouth of the tunnel for 11 all these. But I think it is. It served us very 12 well requiring everything to be a contract between 13 the company and the institution, not between the 14 individual and so we don't have any interactions 15 that aren't between Mayo Foundation and the 16 company; and this is where the standards for it 17 must be publishable and it's not publishable we're 18 not in the contract research business for that 19 purpose. 20 CHAIRPERSON MARSHALL: Dr. Wood, thank you 21 very much for a wonderful presentation and for 22 entertaining questions. 60 1 DR. WOOD: Thank you. 2 [Applause.] 3 CHAIRPERSON MARSHALL: I hope that you 4 might be able to join us for the next hour if you 5 have time for discussion. We would love for you to 6 interact with us during this time as well. 7 And if someone is here from the hotel to 8 remove the podium from the front of the desk, that 9 would be helpful. 10 [Brief recess.] 11 CHAIRPERSON MARSHALL: If we could 12 reconvened a meeting, if we have quiet in the room, 13 please. Our official break is not for an hour. If 14 you would like to step out then please do so 15 quietly. 16 I'm going to use the lavaliere because it 17 seems as though my microphone is the culprit. So 18 he cannot hear me, then please let me know. And if 19 I make any untoward asides, please ignore them. 20 I have been remiss, oh, he is not here. 21 Jim Taggart I will wait until later to introduce 22 Jim to you. 61 1 I do not, however, need to introduce Mark 2 Barnes who has chaired our working group on 3 financial relationships, and as you know, from our 4 previous meetings has done a stellar job at that. 5 His group has been working hard. We are coming, I 6 think, close to a conclusion in terms of, at least, 7 the financial relationship component of conflict of 8 interest. As you know, there are many sorts of 9 conflict of interest. I would like to turn the 10 floor over to Mark. 11 MR. BARNES: Thank you, Mary Faith. 12 I'm here today to report on the latest 13 iteration and hopefully the last iteration to be 14 approved by the committee of all comments from this 15 committee to the Secretary, in regard to the draft 16 and on guidance that was promulgated now quite some 17 time ago before the present administration in 18 regards to financial conflict of interest that was 19 written not only by Stuart Nightingale -- 20 There is a process that we've engaged 21 since the last meeting. What has happened is that 22 based upon the comments made at the last meeting -- 62 1 about the basic principles and why and policy and 2 conflicts of interest. We went back to the drawing 3 board and we did another iteration of the draft 4 letter -- the draft comment letter that was 5 circulated to the committee I think about a month 6 after our last meeting. There were comments on 7 that draft and the comments of the draft resulted 8 in the draft that is before you now. 9 There were comments received from a number 10 of members of NHRPAC on what will be the 11 penultimate draft of the comment letter. And each 12 comment was considered. I printed them all out. I 13 looked at them together. I compared and contrasted 14 what everyone tried to say I tried to include what 15 everyone wanted me to include as long as it did not 16 conflict with the underlying message of the 17 document and as long as two people did not say 18 different things about the same line, which did 19 happen sometimes, and I had to use discretion to 20 choose what I thought would be suggestive of the 21 spirit of the document. 22 I want to highlight some of the major 63 1 changes in the document and major issues that we 2 have yet to look at. But let me make a couple of 3 brief comments in terms of things that ought to 4 focus our attention if Dr. Wood's comments did not 5 focus us enough on this issue. 6 One is that I think it would be wise, and 7 I would suggest, certainly, compliance hospitals 8 and medical centers and physician group clients 9 that they read closely the entire findings of OHRP 10 in regards to the Johns Hopkins studies; because 11 the findings are not simply about the particular 12 study. They are in fact very much about the 13 process of human subjects research approval at 14 Johns Hopkins. There are a couple of things buried 15 in those findings that bear noting for anyone 16 concerned about human subjects research. 17 One is that there was a finding and this 18 is posted on the OHRP web site that the letter to 19 Hopkins -- and this is important, not for today's 20 discussion, but for tomorrow's -- that there was a 21 the lack of consideration of the privacy and 22 confidentiality of human subjects in the course of 64 1 the IRB approval process which is certainly 2 relevant to our discussion at HIPAA tomorrow and 3 the effect of HIPAA on human subjects research. 4 But for today's discussion there was also 5 a finding that there was a failure in some cases 6 for IRB members who had conflicting interests, 7 conflicting financial interests to recuse 8 themselves from the IRB consideration protocol in 9 which the IRB member's interest was affected. 10 There are more than 30 findings in the OHRP 11 findings in regards to Johns Hopkins. I encourage 12 all of us to read those and to use it as a 13 compliance checklist for what you're doing what 14 you're not doing in your process, and certainly the 15 conflict of interest finding ought to come home to 16 all us and we should take a to heart. 17 The second thing that has occurred which 18 we actually referenced in a new paragraph in the -- 19 what I hope will be the final draft of this is the 20 fact that there also had been, since we last met, a 21 consideration of the issue of a serious and 22 significant consideration, the issue of 65 1 institutional conflicts of interest by the 2 financial services industry. 3 The National Association of Securities 4 Dealers has in fact issued draft guidance and I do 5 not suggest that we try to comment on their draft 6 guidance -- 7 [Laughter.] 8 MR. BARNES: -- as we have enough trouble 9 with coming to consensus on the HHS guidance. But 10 interestingly, the NASD which is the trade 11 organization, the trade association for securities 12 firms and research around the country has looked 13 very carefully on promulgated draft guidance about 14 the issue of when a research analyst and his or her 15 firm owned shares of stock, owned financial 16 interest, have significant financial relationships 17 to companies, to private companies, whose shares 18 they are essentially recommending, endorsing, or 19 peddling. 20 And although the guidance is interesting, 21 and I encourage you to look at it on the NASD web 22 site that in many cases they are struggling, the 66 1 NASD is struggling in their draft guidance with 2 many of the same issues with which we have been 3 struggling. For example, what amount of 4 disclosure, should they be required, are there 5 minimum thresholds for disclosure, how do you 6 divide an institutional interest or not? And this 7 is open for comments and comments will close on 8 August 15 before the NASD. And I bring that to our 9 attention only to say that there are institutional 10 conflicts and the relationship between employees 11 and their institutions -- between persons 12 affiliated with the institution and the 13 institutional interest is an issue that emerges not 14 simply in the context but it promotes another 15 context as well where there are, not lives at 16 stake, but certainly financial interest applied to 17 individual investors and I should they add that -- 18 grapple with this is that there were some adverse 19 events especially with the flop in a stock market 20 and especially in high-tech stocks in which it was 21 clear or it was alleged that there were firms, 22 financial services firms that were recommending 67 1 shares and research analyst that were recommending 2 companies when in fact -- but those research 3 analysts in investment firms had significant 4 sharers or stakes in those companies even though by 5 all rights and indications the time for 6 recommending those companies had long passed. 7 And this is referenced again in what I 8 hope will be the final draft of the letter. 9 Now, let me just turn for second to review 10 some of the major features of what we are endorsing 11 if we do endorse, and decide as a body to send this 12 letter on to the HHS secretary. 13 First of all, it is important that we do 14 recognize institutional conflicts of interest as a 15 significant issue in regards to the conflict of 16 interest analysis. We endorse the focus by Dr. 17 Nightingale, Dr. Koski and others on the issue of 18 examining institutional conflicts of interest 19 within the context of all conflicts of interest. 20 We endorse the idea of there being a 21 conflict of interest committee or body that would 22 be an adjunct to the IRB but independent of the 68 1 IRB, composed of people who are able, who have the 2 professional background and expertise to evaluate 3 these conflicts of interest. 4 We endorse the idea that there ought to be 5 some kind of minimum threshold put on the 6 examination of conflicts of interest although that 7 minimum thresholds is not defined in our letter. 8 We do reference in our letter the fact that more 9 and more institutions are moving towards 10 calibrating their minimum thresholds and their 11 disclosure policy to be in line with the public 12 health service thresholds of $10,000 or 5 percent 13 investment. 14 We also endorse the idea which I think 15 significantly goes further than what Dr. Wood was 16 talking about and certainly what most institutions, 17 in fact almost all institutions, that I have ever 18 counseled or looked at which is to say that part of 19 compensation that ought to be disclosed not to be 20 looked at it includes the compensation within the 21 context of the research contract itself. So, in 22 other words, it is not simply the emolument, the 69 1 honoraria, the tryst, the financial patent, it also 2 is the compensation for the research or any 3 institution that is embedded in the research 4 contract itself, particularly when that 5 compensation exceeds the fair market value of the 6 research services that are being rendered by the 7 institution. 8 I just want to flag that, we have 9 discussed it before, but we are pushing the 10 envelope in that regard. I think it is entirely 11 appropriate. I think that most of us think it is 12 appropriate to look at that but that certainly is 13 -- and it goes to the issue, by the way, of so- 14 called "enrollment bonuses" that are paid to some 15 investigators by some companies, by some other 16 research sponsors. 17 I also want to point out some of the 18 differences between some of the -- or amendments to 19 this draft as opposed to the draft that we looked 20 at, at our last meeting. 21 One thing that we have made clearer in 22 this draft is the issue of disclosure of the actual 70 1 conflict, of the actual financial interest to the 2 research subject. What we have endorsed here is 3 certainly the idea that the conflict of interest 4 committee that there should be full disclosure of 5 the researcher and the institution and the IRB 6 members to the conflict of interest committee who 7 would examine and look at those conflicts. 8 We also have again endorsed the idea of 9 there being some kind of minimum threshold, 10 although we do not attach a dollar limit to it. 11 Bob Levine would like us to, but he was not bold 12 enough to offer a suggestion as to what he would 13 like that threshold to be and I certainly did not 14 venture one. 15 We also say that the conflict of interest 16 committee and the IRB should look at essentially 17 the degree of risk that that financial conflict, 18 that particular individualized, case-by-case, on a 19 case-by-case basis the financial conflict of either 20 the institution for the researcher or the 21 researchers proposed and should calibrate 22 disclosure to the patient to be in line with the 71 1 degree of risk, so in the most risky circumstances, 2 for example, presumably there would be disclosure 3 of the actual interest which again goes further 4 than what Dr. Wood was talking about in terms of 5 the Mayo model. But on the other hand where the 6 financial interests are more tenuated presumably 7 there could be what we have termed "generic 8 disclosure." The fact that there is a process in 9 the institution that there was a financial interest 10 that was flagged but that there also were conflict 11 management strategies in place, or in processes, to 12 avoid there being any adulteration of either 13 scientific integrity or of informed consent. 14 To endorse the idea again that there be -- 15 we have not said that there should be disclosure of 16 each and every share of stock. What we have said 17 is that there should be a case-by-case analysis. 18 What we have also said, very importantly, 19 I think, and I do want this to get lost either in 20 what we say or in what Dr. Wood was talking about, 21 and that is that disclosure is not enough. 22 Disclosure is not enough. The primary 72 1 responsibility is not to disclose the financial 2 conflicts of interest. The primary obligation of 3 the researcher and of the institution and of the 4 IRB is to manage the conflict of interest, to 5 manage it to a level that is below the level of 6 what would pose as a significant risk to the 7 research subject. 8 And we put that management obligation 9 first, we put disclosure second. Because, again, 10 as one of the audience members pointed out, in 11 fact, as a couple of them pointed out, even when 12 there are financial interests disclosed, does that 13 really dilute the willingness of participants to 14 engage in research? Usually not, I think in most 15 of our experiences, and in fact those who know more 16 bear a greater responsibility and that would be the 17 conflict of interest committee and the IRB. 18 In the draft there are a couple of 19 additional things. I want to point out that we 20 received several comments including from Susan 21 Kornetski from Bob Rich and from others and from 22 Adil Shamoo, that were respected and I tried to 73 1 include in essence, but the basic comment and there 2 were enough of us to comment on it, I wanted to 3 bring to the committee's attention, there were 4 those of us in the comment period who said that the 5 IRB should be -- that we should suggest that IRB's 6 should actually not be able to overrule the 7 judgment of an internal conflict of interest 8 committee. And in fact that IRB's must bow to the 9 wishes or the suggestions, recommendations, I 10 should say, of a conflict of interest committee. 11 That particular suggestion was not included in this 12 draft, it was included in a different forum, the 13 idea was included, and you will see the idea 14 reflected in the redline version that you have in 15 your notebook in front of you, but why was it not 16 included? It was not included for three reasons. 17 First of all, as we sit today, IRB's have 18 full legal responsibility to pass on informed 19 consent. Conflict of interest committees have no 20 legal status. So we cannot be in the position of 21 saying that IRB's which are there for the legal 22 responsibility and moral responsibility for what 74 1 they are passing on that they must bow to someone 2 else's wishes, they have to be free, both in the 3 legal or ethical matter to decide themselves what 4 should be on an informed consent form and what 5 should not be on the informed consent form. 6 That is not to say that they should not 7 take extremely seriously the recommendations of a 8 conflict of interest committee. In fact, on any 9 kind of risk management strategy or administrative 10 oversight out of the IRB itself one would -- and I 11 say in the draft that is unthinkable that an IRB 12 would ignore the recommendations of a conflict of 13 interest committee, but in fact the IRB cannot 14 simply advocate its responsibility to a COI 15 committee at least as the legal responsibilities 16 are currently configured. 17 Secondly, as many people said, this 18 guidance -- this draft interim guidance promulgated 19 by HHS is meant to be guidance and not regulations 20 and therefore I hesitate to say particularly when 21 COIs are not embedded in the law yet other then 22 they will be, eventually, I hesitate to say that 75 1 somebody must do something since in fact we reserve 2 in our letter the word "must" for those 3 circumstances that are currently legally required 4 and we are careful to do that in our letter. The 5 word "must," as Elliot clarified early on for us, 6 the word "must" means that you really have to do it 7 because it is required by law; "should" means you 8 have an ethical duty to do it; and "may" means that 9 that is a possible way of resolving or fulfilling 10 either a legal or an ethical responsibility and 11 those words are carefully used throughout the 12 draft. 13 And, the third reason that I did not 14 include it was really a policy reason, and that is 15 that we are assuming in making those comments the 16 COI committee is going to be tougher than the IRB. 17 But that may not be the case, and the IRB has got 18 to be free to beat tougher than the COI committee, 19 in regards to evaluating financial conflicts of 20 interest and informed consent. 21 Finally, let me say this, the one set of 22 comments that I was not fully able to -- and Bob I 76 1 do not want to put you on the spot and I apologize 2 for this, but the one set of comments that I could 3 not include completely, although I did try to 4 respond to, insofar as what is consistent with the 5 guidance were some of those of Dr. Rich on this 6 committee. And I do not what I speak for Dr. Rich, 7 he is a big boy, he's bigger than I am, and I am 8 sure he can speak for himself. But essentially 9 there was -- and this is something that has been 10 expressed not only by Dr. Rich but by many others 11 outside of this committee, there was a feeling -- 12 there has been a feeling from various associations 13 that we should not -- it is not time to the 14 government to move, the government should wait in 15 terms of the draft interim guidance, the government 16 should wait for the private associations to do 17 their voluntary work. And I think that many of his 18 comments or some of his comments reflected that. 19 I think it was my sense and I think it was 20 the sense of most people in NHRPAC that the time 21 horizon is short, that the integrity of research is 22 only at stake in regard to the issue of financial 77 1 conflicts of interest and that the time for 2 government to move and for this committee to act is 3 really now. And not to wait, not to save the 4 private association results should not be respected 5 and looked at when they are finally issued, but 6 that we should not really wait for those in order 7 to issue their own guidance. 8 What I did do in the draft that tried to 9 be respectful of what various people -- including 10 but not only Dr. Rich -- had suggested that it is 11 more clear, I think, in this draft that we are 12 asking that HHS really regard this as guidance and 13 not as regulation. And that guidance not be 14 interpreted by OHRP as being regulation and that is 15 contrary to what other experiences have been in the 16 health-care industry when guidance comes out and 17 immediately is interpreted as regulations. 18 Am with that I think I will turn it back 19 over to Mary Faith. 20 CHAIRPERSON MARSHALL: Thank you, Mark. 21 Can you all hear me? No. 22 That was a beautiful summary. Thank you 78 1 for bringing all of us up-to-date from where we 2 were last time and thank all of you committee 3 members who responded to the working group draft. 4 I am sure that there will be fair amount of 5 discussion. 6 Bob, I would like thank you for your very 7 thoughtful input that you gave to us, beautifully 8 written, beautifully worded. 9 What I would like for us to do at the end 10 of the hour, or after I should say, the half-hour 11 or the 25 minutes is, I would like to come to 12 closure of this part of our work and I understand 13 that we may not achieve consensus, that there may 14 be dissenting opinions that would be incorporated 15 into our final product, and that's fine. But I 16 would like to bring closure to this within the next 17 half-hour. So I will entertain comments and we 18 will move forward expeditiously. 19 I have Abbey, Susan, Adil, and I think we 20 will give Bob the first word. 21 DR. RICH: Thank you, Mary Faith. I would 22 like to begin by saying, for the benefit of those 79 1 of you who did not seen my comments, that I am 2 deeply respectful of the work of the working group 3 about this and there was in actual fact very little 4 of the summary of materials that Mark has just 5 presented with which I disagreed. My problem is 6 really a problem of what guidance from a federal 7 regulatory agency except that guidance is usually 8 issued as to an explication of federal regulations. 9 So the regulations are put into the law through a 10 process that is very well-defined and then in order 11 to interpret those regulations oftentimes guidances 12 are developed to help institutions understand what 13 the regulations actually mean. 14 I think there has been numerous occasions 15 particularly in recent years where unfortunately 16 guidance has gotten out in front of regulation and 17 I think that was a part of the problem that in fact 18 to be candid OPRR actually had with the scientific 19 community when there were things that were issued 20 as guidances or as policy that in actual fact the 21 statutory authority or the regulatory authority as 22 promulgated through the Federal Register and 80 1 through the usual process was not at all clear. I 2 think if one takes a look at the process by which a 3 federal agency usually issues regulations and then 4 develops guidance is it is somewhat different from 5 what we are seeing here. And that has been my 6 major concern. 7 I think the concern of a large number of 8 individuals in the community, most of whom endorse 9 the bulk of the materials in this document and in 10 actual fact, my major problem with the whole 11 document was with a simple paragraph, which said, 12 essentially, NHRPAC rejects the thoughtful comments 13 that have been received from a large number of 14 institutions, I think, to its disservice, from my 15 perspective, dismisses them rather out of hand when 16 I believe those thoughtful comments are part of the 17 regulatory process, part of the rulemaking process, 18 and the process for OHRP is very well spelled out 19 in administrative law and I do not think it 20 incorporates guidance in advanced regulation. 21 At the very least I think there are 22 improvements in this final draft, since I have been 81 1 on the country I just saw it this morning for the 2 first time, but I am appreciative of what Mark has 3 tried to do to improve it. I do believe that if it 4 is to be endorsed by the committee at least from my 5 perspective NHRPAC should not be seen as a 6 monolithic entity with which there is no dissent. 7 And it sort of suggests that NHRPAC takes issue 8 with these points. Well, maybe some members of 9 NHRPAC do and maybe even most of the members of 10 NHRPAC do but not all members of NHRPAC do. And I 11 believe that the language needs to be respectful 12 all of some dissension with the process, not with 13 points but with the process. 14 CHAIRPERSON MARSHALL: Thank you, Bob. 15 DR. MORENO: A point of clarification 16 perhaps from you or from Greg, or somebody else, 17 perhaps Kate, is it accurate that the process of 18 promulgating guidance differs from that which has 19 taken place with respect to this matter as far as 20 OHRP is concerned, or DHHS is concerned? 21 CHAIRPERSON MARSHALL: I will let Greg 22 speak for OHRP. 82 1 DR. KOSKI: No, I do not believe that is 2 true. In fact, the process for development of both 3 guidance and rules, okay, os to generally seek 4 broad public consultation and incorporate that 5 feedback into the process. Ultimately, as Bob has 6 pointed out, there is a full, legally required 7 procedure that certainly OHRP is very well aware of 8 and that is required specifically for issuing any 9 new rules and so on. There is some, I think, 10 ambiguity I guess within government as to what to 11 call certain things, you know, how you get 12 information out and of all that. 13 Certainly, in this instance I think 14 there's been some perhaps misunderstanding or 15 perhaps mischaracterization of the status of the 16 draft document that was put out in order to 17 stimulate public discussion which I think has been 18 very effective in doing. At no point was there 19 ever any intent to issue that as a formal 20 requirement. So, in fact, it did not deviate at 21 all from what I would be a normal expected 22 procedure, but nevertheless, that does not bar from 83 1 being perceived in that way by certain parties 2 which I think was perhaps the case. 3 So that, again, what we would expect to 4 within the department would be to again take the 5 council that has been provided not only from this 6 committee but although independently outside of 7 this committee from the very professional 8 organizations and the individuals that share 9 interests and then construct appropriate documents 10 and issue those through the appropriate processes 11 in concert or in compliance with the Administrative 12 Procedures Act and all, so, that's exactly what we 13 intend to do. 14 CHAIRPERSON MARSHALL: I have a question 15 for Bob and that is the fact that aside from your 16 critique relative to the specific wording about the 17 input that NHRPAC received and the fact that we may 18 take issue and your point being that not all of us 19 do take issue. I think that point is well taken. 20 My question, Bob, it is that the letter I 21 think does reflect advice to the Secretary through 22 the Assistant Secretary that other organizations, 84 1 as we know the double AMC, the AAU are working very 2 hard at coming up with other solutions to this 3 evolving problem. And I think that that is well 4 spoken pay and I think that it is spoken seriously 5 to in the letter and I wonder whether you feel that 6 that is adequate in the sense of advising the 7 government that any process that it has in terms of 8 developing guidance and issuing guidance, how it 9 conceives of guidance should be iterative and 10 responsive to these other initiatives. 11 DR. RICH: To the extent that it is simply 12 understood as a dialogue, I do not have a problem 13 with it. But my problem is that what I understand 14 in this document is that NHRPAC is rejecting the 15 process of dialogue and saying that it is time for 16 government action. And by "action" I usually think 17 of it in terms of a regulatory process. 18 I do not know what OHRP or HHS regard as 19 action short of a regulatory process that did not 20 involve something -- some "must"s as opposed to 21 some "should"s and "may"s. But I take it from this 22 matter to be a call for must. To be a call for 85 1 things that the government should insinuate itself 2 short of the formal regulatory process or in 3 advance of the formal regulatory process and should 4 not wait for a formal regulatory process I do not 5 think that that is wise. 6 CHAIRPERSON MARSHALL: Thank you. 7 I'm not sure that I necessarily agree with 8 at least my take on what we as a committee are 9 saying, and if we need to strengthen that, then I 10 think we should. Because I think it would be very 11 unfortunate and I hope it is necessarily spelled 12 out that we feel as though, you know, again, that 13 for the government to be silent on this very 14 important issue sends the wrong message to the 15 community, the scientific community, to the 16 research participants of the world, and I think 17 that, again, maintaining and fostering public trust 18 is perhaps the larger goal here in addition to 19 working through a mechanism for dealing with 20 financial relationships. 21 Okay. And, Greg, I will give you the 22 floor and then I have Bob, Abbey, Susan and Adil. 86 1 Dr. KOSKI: Just a comment which is 2 directly on point to Bob's concern where in the 3 letter it says that there NHRPAC would ask and 4 expect that HHS not portray or regard the guidance 5 as a regulatory requirement, a phenomenon that has 6 occurred in the past in regard to other guidance 7 documents, even where government officials wouldn't 8 read that, I think we understand and know exactly 9 what the intention is there. 10 PARTICIPANT: [Off mic.] 11 DR. KOSKI: Right. So I think we are 12 certainly having seen -- not only now this comment 13 from NHRPAC but also from other agencies, we are 14 certainly sensitive to that. To go back to your 15 original point, though, about guidance being an 16 explication of the regulation; the regulation, 17 basically the common rule under which we operate, 18 or the corresponding part of the FDA regulations, I 19 think make it very clear that we have to consider a 20 host of issues that have a direct impact on the 21 well-being and interests of the participants of 22 research. 87 1 One of the things that we noticed from the 2 outset from the office conference is that this is 3 an area under which the regulations clearly defy 4 that there has been inadequate explication in terms 5 of providing the kind of guidance that is necessary 6 to help IRBs, institutions, investigators work in 7 that area. So we are very mindful of the ongoing 8 work of doubling in fee and a host of other groups 9 that are working on that -- overly concerned about 10 it. 11 CHAIRPERSON MARSHALL: Abbey. 12 MS. MEYERS: Yes, I want to reiterate, you 13 are very lucky to have Mark Barnes on this panel. 14 This is just a superb piece that will be relied on, 15 I think, for many years in the research community. 16 But I have only one problem, and that is the Mercy 17 Hospital paragraph. And it comes because my family 18 has been in many studies and in those studies I 19 know that when I put the life of my children in the 20 hands of this doctor at university, and completely 21 trusting him, and I would not daresay because of 22 that little line in that Mercy Hospital paragraph, 88 1 oh, tell me how much stock you own. In function, I 2 would lose my relationship with him, if I am scared 3 to ask questions. I would fear that and so the 4 paragraph itself is intimidating to a parent or to 5 a patient who really does not want to say, by the 6 way, are you a member of the Communist Party? 7 [Laughter.] 8 MS. MEYERS: And basically, I guess the 9 message that it sends really, trust this conflict 10 of interest committee at the hospital because we 11 are really smarter than you. And we're handling it 12 so you can put the life of your kids in our hands 13 also. And so I am really bothered. I think that 14 the paragraph should say, it does not have to give 15 the dollar figure, but it should say, the 16 investigator owns stocks, the university owns 17 stocks, that the contract with the company says 18 that no paper will be published unless the company 19 reviews the paper and agrees to it. 20 It should also say that the pediatrician 21 got paid $5,000 for the referral and that is the 22 most important thing that can be in this paragraph 89 1 because they trust their pediatricians, and when 2 they are referred for clinical trial, they think it 3 is for the sake of their child. And when they get 4 to the hospitals they find out that the 5 pediatrician has been paid off. It is really an 6 eye opener. So I think that paragraph is just too 7 disturbing to go through the way that it is. 8 MR. BARNES: Abbey, I hear what you are 9 saying, but I just want to point out the framing of 10 this. This is different than the context of the 11 Mercy paragraph in the draft that was presented at 12 the last meeting and it is different because there 13 is a paragraph, that precedes the paragraph that 14 contains the Mercy paragraph, which makes it clear 15 that in fact the Mercy example is only for those 16 situations in which the financial interest is so 17 attenuated that the COI and the conflict of 18 interest committee and the IRB is not choosing to 19 mandate the specific disclosures of each and every 20 share os stock. 21 So, for example, in the paragraph above, 22 the new language is that the IRB and the conflict 90 1 of interest committee should be aware -- should 2 calibrate -- should look at the possible conflict 3 and the nature of the conflict and the conditions 4 and extent of disclosure should be calibrated by 5 the COI committee and the IRB to correspond to the 6 level of risk that the conflict poses so that there 7 is, for example, in the application of that 8 principle if there is, for example, $5,000 received 9 by a pediatrician as a referral fee, then that is 10 enough of a direct financial interest that that 11 certainly would be disclosed and one would not 12 revert to the Mercy paragraph. The Mercy paragraph 13 is only used as an example of what we have called 14 generic disclosure rather than specific and generic 15 disclosure is reserved for those situations in 16 which the financial interest is quite attenuated 17 and not direct. 18 Okay. That is one thing. 19 The second thing is that also taking into 20 account some of the commentary and discussion at 21 the last meeting, there is also a new sentence -- 22 and the reason is not redlined in here is because 91 1 it was redlined in the previous draft you got about 2 two months ago, and that is that in regard to this 3 issue of particular disclosure is the researchers 4 and institutions must recognize that when they have 5 direct personal investment in a research item or 6 device, research subjects' safety and independent 7 decisionmaking must take priority over researchers 8 and institutions financial privacy. 9 So I want to just point out that both 10 before the Mercy paragraph and after the Mercy 11 paragraph your point of view, I thought, had been 12 really taken into account here because I really -- 13 the way that I interpreted the letter as it stands 14 now, is that the Mercy paragraph is really reserved 15 for those situations in which, for example, the 16 physician might have shares in a mutual fund or a 17 blind trust where he or she may have some financial 18 relationship but it is quite diluted. And that 19 would be what the Mercy paragraph would be used 20 for. 21 MS. MEYERS: I am more or less afraid that 22 that paragraph is there and that it is going to be 92 1 relied on as the example. I would feel more 2 comfortable if it were taken out completely. The 3 rest of the paper is inadequate. 4 DR. FLEISCHMAN: I want to speak to 5 support Abbey's position here very staunchly. At a 6 minimum I think we need an additional paragraph 7 that describes what the IRB ought to put into the 8 consent form if there is a specific focused 9 conflict that they are concerned about. My concern 10 in reading this is having spent 25 years rewriting 11 consent forms on IRB's that this is very confusing 12 as a paragraph. To me, as the research subject 13 potentially, and to me as an IRB member, I would 14 not be satisfied that the level of understanding of 15 the subjects would be sufficient to meet the 16 standards that most IRB's have created for other 17 parts of the document. 18 So I think we need two things at a 19 minimum. One is an indented paragraph that 20 describes the kinds of problems that are in that 21 paragraph above and how we would recommend to an 22 IRB to deal with those kinds of conflicts and that 93 1 might make Abbey and myself feel more secure on 2 that. And the second is, Dr. Wood this morning 3 talked about the trust issue and we're focusing 4 much on institutions as well as investigators and I 5 guess inherent in that is that I'm not certain 6 about Mercy Hospital and I would like to trust it 7 more. 8 So I would like to really make this 9 paragraph much more clear, that we are a little 10 worried here Mercy Hospital about this problem. 11 We're doing everything we can to be sure that you 12 personally and your child who are the subject of 13 research are being protected and we have this 14 process in place that is in place to do that. 15 And if you want to know more about the 16 process, you know, let us casted. But it is just 17 not clear to me. 18 CHAIRPERSON MARSHALL: Did you want to 19 respond to that, Mark, or shall be continue on? 20 Okay. I have Susan, Adil. 21 DR. KORNETSKY: My comment is about 22 something else. So if you want to continue to 94 1 discussion and then come back to me, that is fine. 2 CHAIRPERSON MARSHALL: Denyse, are you on 3 point? 4 DR. THORNLEY-BROWN: I too have had a level 5 of discomfort about the Mercy Hospital paragraph. 6 Part of it is the vagueness. It is difficult to 7 understand even for people who are educated and 8 involved in clinical research. But the thing that 9 bothers me more if that sentence, if you would like 10 more information, blah-blah-blah, please ask the 11 researchers or the research coordinator. If there 12 is an IRB and if there is a conflict of interest 13 committee that has been assigned to address these 14 things, why not refer the subject to these 15 committees rather than a PI or other people 16 involved -- directly involved. I think, as Abbey 17 said, people are very intimidated about asking the 18 doctor. If they can ask someone else in another 19 committee like in the conflict of interest 20 committee, that might be easier. 21 CHAIRPERSON MARSHALL: Susan, Adil and 22 Felice. 95 1 MR. BARNES: I hear what Abbey, what Alan, 2 and what others have said. And we could certainly 3 review this paragraph and change it, I mean, if you 4 have particular suggestions, I like be happy, you 5 know, to include them, Alan. 6 You know what should humble us a little 7 bit is that if we have trouble as a committee 8 trying to come up with a paragraph like this or a 9 paragraph for what we have termed as "specific 10 disclosure" then this really goes to Bob's point 11 that it certainly is hard for institutions out 12 there to try to implement these thing when, again, 13 we had trouble drafting a paragraph as a model. 14 You know, what I would suggest, perhaps, 15 is one of two options. Either we can -- we can 16 certainly include what Denyse has referred to as 17 referring the patient or the central research 18 subject to the IRB or COI as sources of 19 information, but we either can simply eliminate the 20 Mercy paragraph example, we could do that, or we 21 should really go back and try to write paragraphs 22 that really captures the specific disclosure 96 1 example and also that references, and we can 2 certainly do this in very practical ways in which 3 institutions can in fact manage conflict of 4 interests which would be, for example, outside 5 monitors of the informed consent process, outside 6 data monitors, close IRB attention to the SMB 7 reports, data tech monitoring board reports, 8 outside review of interpretation of data and 9 reports. I mean, these are all things that we 10 could certainly put into the document. So those 11 are, you know, I just put those open as two 12 possibilities, but I'm certainly open to any 13 changes in the language. 14 CHAIRPERSON MARSHALL: I would just like 15 to speak to that and then perhaps we can move on. 16 One of the things that we have been committed to as 17 a committee is providing concrete advice to those 18 whom we are supposed to advise, including research 19 subjects and IRB members. So I think when we can 20 do something like provide a draft paragraph that 21 might be a template, that would be helpful. 22 Perhaps during the course of the day 97 1 today, or at least by the end of the meeting 2 tomorrow, we might ask Mark, Abbey, perhaps Alan, 3 other members of the committee who might be 4 interested in drafting an additional -- working on 5 the Mercy Hospital paragraph, adding one for an 6 honest attenuated financial relationship. And, 7 Bob, if you had suggestions in terms of tempering 8 the language, then we could do that and then by the 9 end of the meeting we can have a document that we 10 are ready to move forward with. I would like to 11 make that concrete suggestion. 12 And I have -- Elliot, was that on point, 13 or -- I do have you on my list. Okay. Go ahead. 14 DR. DORFF: I just have some suggestive 15 language along Bob's line. That paragraph, just 16 before the sentence before the last. "The issuance 17 of non-regulatory suggested best practices guidance 18 through an interim guidance document does -- that 19 document's ultimate content inconsistent with the 20 goal of prudent government action on a rapidly 21 evolving issue" and then I would just simply add, 22 "Or with continuing input from individuals and 98 1 professional organizations. In that spirit NHRPAC 2 would ask and expect" and so on. 3 CHAIRPERSON MARSHALL: Thank you. Kate 4 has duly noted that. Thanks Elliot. 5 And I have Susan, Adil, Felice. 6 DR. KORNETSKY: Mark, I just wanted to 7 thank you very much for taking into consideration 8 my concerns. I feel a lot more comfortable with 9 them. I still do share the concerns of Dr. Rich 10 that this is not -- regulatory, but also trust Greg 11 that they hear us. So, I think I'm fine on that. 12 The one thing that I did want, you refer 13 to here a diagram in Exhibit A which we don't have. 14 And I remember the initial one, at least in my mind 15 was problematic. And I think that I would like to 16 review that because I, again, am very concerned 17 about the relationship of what to put on the IRBs. 18 And perhaps as we talked about with examples so 19 that it isn't looked at, you know, a picture speaks 20 a thousand words sometimes and I'm afraid that this 21 will be the diagram, this is the way we need to do 22 it. That perhaps we may want to have two different 99 1 models, or ways of doing things. Thank you. 2 CHAIRPERSON MARSHALL: Thank you, Susan. 3 Adil and then Felice, and then I would like to open 4 the floor up. 5 DR. SHAMOO: Thank you. I want to echo 6 everybody's compliment to Mark. It's a brilliant 7 job in trying to put this document together. I 8 would like to see, as Mark knows, a greater 9 disclosure to patients and there should be really a 10 threshold amount. Otherwise, universities and 11 research institutions will have such a latitude 12 that it will be ridiculous. 13 Some institutions, as you know, Harvard 14 wanted to modify their conflict of interest policy 15 to move it up to $100,000, and there was an 16 outbreak in the media and among academic 17 institutions they backtracked. So institutions are 18 already thinking 100,000 is okay, some institutions 19 would think 100 million is okay. 20 Having said that, I would like to just 21 clarify, since you put me in Bob's and Susan's camp 22 about that conflict of interest relationship to the 100 1 IRB, my comments were very clear, and that is, if 2 the conflict of interest committee of the 3 institution being this proposal is coming through 4 with entangled conflict of interest and they're 5 rejecting it on that basis, that the IRB should not 6 be able to overrule it. 7 Again, I am on very thin ice having to 8 oppose a brilliant lawyer who is chairing the 9 committee, Mark, and that is, in my comments I 10 said, "I don't see administratively how that will 11 work." Institutions, the -- OHRP officially deals 12 with institutions even though IRB is the legally 13 authorized through the common rule to deal with 14 issues. If the institution chooses not to allow a 15 research proposal to go through, they have multiple 16 ways of stopping it; the chairman of the 17 department, the dean, the president, and I cannot 18 see how an IRB can overrule an institution which 19 deems this is full of conflict of interest and says 20 the IRB should go because the institution doesn't 21 want to apply for that grant proposal. So I'm 22 saying, that sentence is really flawed by logic, by 101 1 precedence, by experience, and the legal 2 relationship that NIH has with institutions, the 3 grants are given to the institutions. Thank you. 4 MR. BARNES: Adil, I thought that I had 5 really included that point. Because I think you're 6 absolutely right. Just because an IRB approved 7 anything, does not -- or a COI committee approved 8 anything, does not mean that the administration 9 anywhere needs to let that study go forward. And 10 administration can certainly decide that they don't 11 want this study. And they don't want to take the 12 money and they don't want to take the 13 responsibility. 14 And that was why I said in one of the 15 sentences that was added here in the section -- I 16 don't know exactly what page it's on, but the 17 section that is subtitled "Financial Disclosure 18 Process COI Committees and Designated Officials" I 19 added the sentence, "that it would be nearly 20 unthinkable as a matter of risk management and 21 ethical behavior that an IRB would ignore COI 22 committee's recommendation on these issues or that 102 1 a health care facility's administration would allow 2 research to proceed if it's IRB had significantly 3 relaxed the recommendation of a COI committee." 4 And I thought that the presumption of that sentence 5 was that the institution always has the -- not only 6 the authority, but really the responsibility to 7 stop a study if the institution's directors or 8 administration really believes that the study is 9 substantially flawed. 10 DR. SHAMOO: But at least to me, for 11 someone who has an accent, I still understand IRB 12 can't ignore the COI committee. And I'm saying 13 there is no way it can ignore the institution's 14 decision. 15 MR. BARNES: And I would agree with that. 16 I think that the institution can certainly 17 overrule, you know, it's own IRB To say -- not to 18 say that the study can go forward, but to say that 19 the study must be aborted. 20 CHAIRPERSON MARSHALL: Okay. Bob has a 21 very quick point and I still have Felice and Greg 22 and then we have about ten minutes left because Dr. 103 1 Fleischman has graciously allocated us 15 minutes 2 of his time. But I want to move on to our ex- 3 officio and our public members. So, please make 4 your points. 5 DR. RICH: I'll make this very quick, and 6 I want to speak directly to Adil's comment about a 7 minimum threshold which I think -- notion. One of 8 the things that we only skirted around is the whole 9 issue of conflicts of interest outside of academia 10 and particularly when one is dealing with things 11 like enrollment bonuses where a -- and where 12 payments and contracts are per patient as opposed 13 to a global contract. One could very easily see, 14 for example, a $500 or $1,000 payment per patient 15 falling below any threshold and actually being a 16 way of completely getting around the problem of 17 disclosure of those kinds of bonuses. 18 So I think setting a minimum threshold has 19 a real danger to it in the sense of them being able 20 to skirt under it by contracts that are on a per 21 patient basis. And I believe we're better served 22 by not being too specific about that, at least in 104 1 this document. 2 CHAIRPERSON MARSHALL: Felice. 3 DR. F. LEVINE: Let me address first the 4 conflict of interest. I think I was in the COI 5 group, being the group of last resort. And I felt 6 comfortable with your explanation. So when Adil 7 and others have reraised the point, I think that 8 role of the institution really make -- the final 9 determination. I think our concern was really in 10 the context in which a CIOS that work really should 11 not go forward or that the conflicts are so 12 substantial that an IRB -- rethink that in such a 13 way that makes the conflict less substantial. So I 14 think that somehow that ultimate judgment for the 15 institution to make that reconciliation might help 16 in that crossing of words. 17 I also think that the Mercy paragraph -- I 18 think we should seek to follow what Mary Faith 19 said. I think we should try to revise it and 20 operationalize it, so we put some real skin on the 21 bones. Because of the emphasis we are putting on 22 conflict management, not just on the determination 105 1 -- not just on disclosure and I think having more 2 sense of how that management process will unfold 3 and the ways that you just really -- Mark, would be 4 extremely helpful. 5 And in that regard I would like us to use 6 the language that Bob Levine would of course 7 emphasize that we should use and that is that it's 8 not just in the consent form. It's a consent 9 process. 10 And, frankly, in the past year and 11 especially since joining NHRPAC, I am struck with 12 how many forms I sign all the time and I'm reading 13 them and I'm seeing what I'm reading, and I'm 14 thinking, but I've got to move on because I've got 15 to navigate this process. And I think I agree to 16 all kinds of things that I wouldn't otherwise agree 17 to because it's time to accept the process. And I 18 assume that many persons in these situations will 19 find the information -- but really want to 20 understand what do you do now if you find out and 21 you're learning this thing as, in a sense, not the 22 11th hour, but the ninth hour, and -- 106 1 PARTICIPANT: You agreed to that? 2 [Laughter.] 3 DR. F. LEVINE: Well, the third thing I 4 just wanted to address, let me just do it briefly, 5 is the issuance of letter. And I'm appreciative of 6 what Bob said. I didn't read the letter. I would 7 always be concerned about guidance stepping ahead 8 of regulation, but I thought we had nearly worked 9 that through on the -- exceptionally well. 10 I read the letter and it was extremely 11 measured, almost a model, in my view, and that is 12 that NHRPAC, we're a body, and we do have a voice. 13 There was lots of use of the words "majority" and 14 "minority" "consensus" it's not unanimity that we 15 are a body, we also have individual acts and 16 expressed in various ways. And I thought this 17 letter really captured the nuance quite well. I 18 think to go on at any greater length about all the 19 differences of our individual perceptions, even my 20 own on COI, I think would really kind of undercut 21 commonality of our voice, but I thought this was 22 really -- I would like to -- 107 1 CHAIRPERSON MARSHALL: Thank you, Felice. 2 Greg very quickly, and then we'll open the floor. 3 DR. KOSKI: Very quickly. In this whole 4 discussion of guidance versus regulation, I've 5 emphasized many times that regulations are 6 basically promulgated in order to either get people 7 to do things that they wouldn't otherwise do that 8 they should do, or to keep people from doing things 9 that they otherwise would do that they shouldn't 10 do. So it's very clear where we need regulation, 11 okay, and that general context. 12 I think as this discussion goes forward, 13 and particularly as we get more input, for 14 instance, from the AANC process, in other words, 15 there will be certain areas where certain processes 16 are identified. And we've heard some of them 17 talked about here, bounties to individuals and all 18 are just so egregious and carry such a difficult -- 19 there may be a requirement for regulations to 20 prevent those in order to make sure that there is a 21 level playing field across the board. 22 In fact, the conference that Mike Wood 108 1 hosted back at Mayo earlier in the spring, this was 2 one of the surprising conclusions from about 80 3 institutions from across the country that in fact 4 when it came to certain points they would rather 5 see regulations because it means everybody is going 6 to play by the same rule. 7 So I think we, at this point, our sense of 8 the fact, that we ought to, you know, go forward in 9 a deliberative manner, get all the input, I don't 10 want anyone to misinterpret my comments, meaning 11 that there will be no federal regulations coming 12 out of HHS with regard to financial relationships 13 and conflicts of interest in human research, but I 14 think we know that there is a process and a time 15 for that. 16 CHAIRPERSON MARSHALL: Thank you, Greg. 17 I'm sorry, committee, I'm going to move forward and 18 ask if there are ex-officio members who would like 19 to ask questions of Mark Barnes or any anyone else 20 in the audience? 21 [No response.] 22 CHAIRPERSON MARSHALL: Then I will 109 1 entertain Alan's question. 2 DR. FLEISCHMAN: Actually, it's not a 3 question, but I rise to Mark's challenge. And as I 4 understand it, Mark, there are three possible 5 scenarios. One is that the conflict of interest 6 committee and the IRB have found that there is a 7 conflict of interest which warrants the research 8 not going forward. 9 The second is, there's a conflict of 10 interest of a level of significance which warrants 11 mitigation, the mitigation having been done and the 12 research should go forward with disclosure. 13 And the third is that there is some 14 potential conflicts of interest, but not at such a 15 level as to warrant disclosure, but to warrant 16 reassuring that the research subjects that the 17 committees have dealt with the problem. Is that -- 18 MR. BARNES: And in the last example 19 providing the research subject with the opportunity 20 to get more information if they really have a 21 particular concern about it. 22 DR. FLEISCHMAN: Well, my understanding is 110 1 that in both the second and the third, we would 2 want the research subjects to have the opportunity 3 to ask further questions anyway. So I would 4 suggest something like this. Every research 5 scientist and physician at Mercy Hospital must 6 disclose significant financial interest in private 7 companies or institutions that may be related to 8 this research study. 9 Our hospital committees have reviewed this 10 information and have concluded that there are some 11 financial relationships between the investigator or 12 the institution with the company that funds this 13 research project. 14 At this point, if it was in the category 15 of significant, we would disclose what that is. If 16 it's not in the category of significance, we would 17 not disclose it. But in both circumstances we 18 would then continue with, however, the committee 19 believes that there are no conflicts of interest 20 which will influence the way you are treated in 21 this study, or in the way the research study will 22 be conducted. 111 1 If you wish to have more information 2 concerning the process of review or these conflicts 3 of interest, please contact whatever. 4 CHAIRPERSON MARSHALL: Thank you, Alan. 5 Stewart, would you like to make any remarks? 6 Dr. NIGHTINGALE: [Off mic.] 7 CHAIRPERSON MARSHALL: Thank you. 8 DR. KOSKI: If I could just introduce, for 9 those of you who don't know Dr. Steward 10 Nightingale, he actually has been instrumental in 11 helping us move all of this forward, and in fact, 12 chairs the working group of the Human Subjects 13 Research Subcommittee that will be working on the 14 recommendations to come forward from this group and 15 other public comments to promulgate whatever. 16 [Laughter.] 17 CHAIRPERSON MARSHALL: Mark, let me ask 18 how you would like to proceed in terms of time? We 19 have closing time at the end today, or would you 20 prefer for us to make time in the schedule tomorrow 21 for a revisit of a new paragraph for us to come to 22 closure on the document with? 112 1 MR. BARNES: I'll tell you what I would 2 prefer if NHRPAC would indulge me on this. What I 3 would prefer to do is basically to suggest the 4 following. That we include Alan's language in 5 place of the Mercy paragraph with appropriate 6 framing. That we include reference to the 7 financial management strategy, the conflict of 8 interest management strategy that I alluded to, 9 that we include the language that Elliot had to 10 meet Bob's point, and, finally that we come up with 11 a diagram that satisfies Susan. 12 [Laughter.] 13 MR. BARNES: And that accurately reflects 14 the content of the letter. And with those, and 15 with the committee basically trusting, I guess, me 16 and Kate, and you as chairperson to make sure that 17 those are included and with those -- to ask for 18 approval of the letter and that we will try to get 19 this out as quickly as possible and probably by 20 some point next week, you know, to everyone in case 21 there are any kind of final objections. But I 22 think that -- I mean, I would prefer that we do it 113 1 that way because we've already been through a 2 lengthy process. I think that we trust each other, 3 you know, in terms of implementing the suggestions 4 of the committee and I would ask for that approval. 5 CHAIRPERSON MARSHALL: Let me just ask, 6 I'm seeing a lot of heads nodding around the table, 7 but I want to ask anyone, including Bob, if you 8 have objections to that way of proceeding? 9 DR. RICH: I'll be happy to accede to 10 Mark's judgment provided that in the one paragraph 11 to which I have particular objection, I think 12 Elliot has contributed something important, but the 13 one other thing which is to say, most members of 14 NHRPAC in a couple of places to make it clear that 15 there was at least -- I don't think that we -- 16 argument very much, but it does make it clear that 17 not every member of NHRPAC saw it exactly the same 18 way. 19 CHAIRPERSON MARSHALL: Thank you. 20 So I think that we have achieved consensus 21 yet again. Thank all of you. Mark and the members 22 of your working group, thank you especially for an 114 1 absolutely fabulous job. 2 [Applause.] 3 MR. BARNES: Mary Faith, can I thank -- 4 there's a University of Chicago law student in the 5 audience, Dan Powell, who dug up the National 6 Association of Security Dealers information for me. 7 So I want to thank Dan. 8 CHAIRPERSON MARSHALL: Please stand up, 9 Dan. 10 [Applause.] 11 CHAIRPERSON MARSHALL: And we are going to 12 take a 15-minute break. We will begin at exactly 13 five minutes after 11. Thank you. 14 [Brief recess taken at 10:50 a.m.] 15 CHAIRPERSON MARSHALL: Before I turn the 16 floor over to Dr. Alan Fleischman who chairs the 17 working group on children as research subjects, I 18 would like to introduce someone to you, and he is 19 James Taggart. Jim, would you mind standing? 20 Jim is a Greenwald Fellow at Johns Hopkins 21 University at their center for Bioethics, I 22 believe, and he's helping us with work on the 115 1 social sciences and non-biomedical research working 2 groups. And, Jim, we are so glad that you are on 3 board and thank you very much for your wonderful 4 help. 5 Now, I will turn this portion of the 6 agenda over to Dr. Fleischman. 7 DR. FLEISCHMAN: Madam Chairperson, I have 8 a question to ask of you before we get to the 9 substance of the conversation because it is 10 relevant to the substance and the process of the 11 working group. And that has to do with the 12 question of dissenting opinions. I took the 13 opportunity recently to reread a book by Jonathan 14 Moreno in which he describes the distinction 15 between consensus and compromise. And I would 16 suggest that we may wish professor Moreno to share 17 that distinction with us. 18 My understanding is, in consensus people 19 may dissent, but the majority or a good solid 20 majority has agreed to a certain direction. 21 This morning you suggested that dissenting 22 opinions will be incorporated into our products. 116 1 Professor Rich asked that we modify some language 2 which says the majority of NHRPAC believes or some 3 of NHRPAC believes, or one or two people, but it -- 4 [Laughter.] 5 DR. FLEISCHMAN: -- but he made the point 6 that we should be respectful of dissenting views 7 and allow members of NHRPAC or working groups or 8 others to have dissenting views and to be respected 9 by not suggesting that it is unanimity in our 10 language. But I do wonder whether it is your 11 intention that as we bring forward documents out of 12 NHRPAC that you will take the opportunity to share 13 all the dissenting views with everybody we're 14 sending our opinions about issues, or will you just 15 share the consensus? 16 CHAIRPERSON MARSHALL: Thank you, Alan. 17 If I can be heard. I guess this is my 18 bias at the moment, and that is, I hope that in the 19 future we will achieve consensus and I do 20 understand that consensus is not unanimity. I 21 think if we did achieve unanimity on everything 22 that there would be a problem in terms of how this 117 1 committee is constituted. 2 [Laughter.] 3 CHAIRPERSON MARSHALL: I guess my sense is 4 that, if there are strong dissenting opinions, that 5 they should be acknowledged within a document. 6 That does not mean that we have to attach a 7 separate document that is a formal dissent, but as 8 we have been working drafts in the past, I think 9 that we can incorporate the idea that those who 10 dissent may be trying to convey or simply the 11 disagreement with a certain point. But I think 12 that we need to be respectful of the breadth of 13 opinion that we have in the room and that when 14 there are great differences that they should be 15 acknowledged. 16 Otherwise, I think it is sufficient to say 17 that we have achieved consensus and I hope the 18 majority of the world understands that that does 19 not mean unanimity. 20 And, Jonathan, can you enlighten us in 21 anyway? Or do you have anything further that you 22 might want to add? 118 1 DR. MORENO: Well, I want to encourage 2 everybody to buy the book now that Alan has 3 mentioned it. 4 [Laughter.] 5 DR. MORENO: Since I might finally sell 6 it. There is no conflict of interest here. 7 [Laughter.] 8 DR. MORENO: I finally might sell a couple 9 though. I think even descriptively consensus -- 10 and there is data on this -- is not always 11 understood as unanimity. And without venturing to 12 the distinctions that one reviewer said led him 13 into alpha state when reading the book, there is 14 one that I think we reflected in our activity this 15 morning, namely that while we might not have been 16 able to achieve substantive consensus or unanimity 17 on everything in the financial conflict of interest 18 report we did achieve procedural consent with 19 respect to, as you put it, Mary Faith, the language 20 that was to be used in characterizing our 21 deliberations and our conclusions. 22 And that I think is often what -- all that 119 1 is needed, I do not think we necessarily need to 2 reach beyond that. 3 DR. FLEISCHMAN: Thank you very much. 4 Let me then put in context our first part 5 of the conversation from the children's working 6 group and that is a draft document which the 7 committee has in front of it. And this morning, I 8 believe, the committee also got a dissenting view 9 from one of the working group members and we will 10 probably, I think, be able to talk more about that 11 as we go on in our conversations, but in your 12 packet today, at the table, there was the 13 dissenting comment. 14 Let me put in context what -- I want 15 everyone to understand, I do not believe it is the 16 most important issue that the working group on 17 children's regulation will deal with in its tenure, 18 but it is a timely issue. It is a timely issue 19 because in April the FDA in its review of whether 20 its regulations were consistent and congruent with 21 the HHS/NIH regulations came to the conclusion that 22 one part of the children's regulations 408(c) was 120 1 not consistent with the FDA regulations; and they 2 could not support that regulation. And let me 3 remind you what that very small part of the 4 children's regulation states. And it is in the 5 document. 6 It states that "if the IRB" -- I am 7 quoting, "if the IRB determines that a research 8 protocol was designed for conditions or for a 9 subject population, for which parental or guardian 10 permission is not a reasonable requirement, to 11 protect the subjects, for example, neglected or 12 abused children, it may waive the consent 13 requirement in subpart (a) of this part and 14 paragraph (b) of this section provided an 15 appropriate mechanism for protecting the children 16 who will participate as subjects in the research is 17 substituted and provided further that this waiver 18 is not inconsistent with federal, state, or local 19 laws. 20 The choice of an appropriate mechanism 21 would depend upon the nature and purpose of the 22 activities described in the protocol, the risk in 121 1 anticipated benefits of the research subjects and 2 their age, maturity status and condition." 3 The rejected this section, in my opinion, 4 not because they believed it was wrong, but because 5 they believed that the law that empowered them did 6 not allow it. That's my understanding of the FDA's 7 statement. 8 The working group reviewed that question 9 and using the following example, were concerned for 10 future mature adolescents. In the late 1980s and 11 early 1990s, when HIV and AIDS drugs were being 12 found to be effective in adults, the physicians 13 caring for adolescents came forward and wished to 14 enroll adolescents in clinical trials with what 15 were drugs that were under FDA regulation, but the 16 research would be funded through NIH clinical 17 trials. IRBs around the country, some opted to use 18 408(c) because some mature adolescents had come 19 forward to be treated clinically for this disease, 20 requesting of their doctors to not inform their 21 parents. 22 Those youngsters would not have allowed 122 1 the clinicians to inform their parents about the 2 behaviors or the diagnosis for which they were 3 being treated. It was perfectly legal for those 4 clinicians to treat those youngsters. 5 However, they could only be enrolled in a 6 clinical trial if there was a process for waiving 7 parental permission and assuring that the 8 adolescents would have a procedure to protect their 9 interests. 10 IRBs interpreted this to mean, in general, 11 that there ought to be some capacity determination 12 of those adolescents to assure that they had the 13 ability to make judgments. They also interpreted 14 these in general to mean that there ought to be 15 some procedural safeguards like ombudspersons, 16 nurses, or social workers, separate from the 17 research enterprise which the adolescents could go 18 to for counsel. Not in lieu of parental authority, 19 but for counsel, so the adolescents would have 20 someone else to chat with that was not part of the 21 research project. And the IRBs were, in general, 22 had to assure that this process went on in a robust 123 1 and rigorous way. And, indeed, IRBs did that. 2 And I believe that IRBs did that without 3 any knowledge that the FDA might have thought that 4 this wasn't the right thing to do. In fact, they 5 were doing it based on the NIH clinical trials and 6 believing that 408(c) was consistent with what they 7 were doing. At least the IRBs I sat on believed 8 that. 9 So the working group rose to this concern, 10 writes this document to share with the FDA our hope 11 that they would reconsider their conclusions and 12 harmonize their structures with the NIH guidelines 13 for a specific small group of mature adolescents 14 for specific circumstances and with specific 15 procedural safeguards which are implied and now I 16 think ought to be specifically argued in a guidance 17 from OHRP as to what 408(c) might imply for such 18 youngsters. 19 And we attempted to write this in this 20 letter and we raised it to the level of NRHPAC's 21 discussion. And as Kate has shared with the 22 committee, the FDA is awaiting our letter. The 124 1 time frame for having given comments has passed. 2 But they have said that they will accept our 3 letter, I assume, as long as we get it in, in a 4 timely manner which means very soon. But that 5 doesn't mean we can't revise it or change it. 6 Now, may I just comment on the specific 7 dissent from one working group member? 8 I think that, and I expect that Ms. Sharav 9 is here and will speak to her dissent. But I think 10 it really is a concern about the protection of 11 children and the role of parents in that regard. 12 And I think it is an honest concern, and I think 13 that I would only caution that the working group, 14 and I believe NHRPAC wishes this to be about a 15 specific group of mature adolescents which we have 16 tried to explain. And if we have not explained it 17 sufficiently, then we ought to explain it 18 sufficiently. 19 It is not an intention to go around 20 parental permission. It is not an intention to say 21 to clinicians that there isn't a role for parents 22 even in those adolescents who come forward and say 125 1 they don't wish their parents involved, clinicians 2 in general ought to consider that serially with 3 adolescents. The American Academy of Pediatrics 4 has said that and most pediatricians would argue 5 for the value of parental involvement in chronic 6 diseases in youngsters. But there does come a 7 point in time where the interests of those 8 adolescents may outweigh involvement of parents in 9 specific circumstances. 10 DR. DORFF: I agree with the substance of 11 the letter, I just have three suggestions. One is, 12 on the bottom of the first page where you are 13 identifying what group of adolescents you're 14 talking about, it's unclear because the regulation 15 addresses, I'm reading at the bottom of the first 16 page, "protecting children specifically neglected 17 or abused children, however, it would be the 18 exceptional situation, if ever, that would involve 19 attending -- from youngsters 10, 11, or 12 years of 20 age. A committee focused, per se, is not in 21 chronological age alone, but rather places greater 22 emphasis on the youngster's level of maturity, 126 1 condition, or status. But the problem is that then 2 the question is, well, you don't need 10, 11 or 12, 3 what do you mean, 13? 4 You know, and what I would suggest to you 5 is that the LA County -- there's a joint commission 6 of the LA County Environmental Association that 7 deals with biological stuff and they have a 8 guideline foregoing life-sustaining treatment for 9 minor patients. And their language, I think, is 10 just much clearer. The principal is that the minor 11 should be part of a decisionmaking process to 12 whatever extent his or her abilities allow. 13 And her comment is: California court 14 opinions and statutes suggest that mature 15 quote/unquote minors will typically include at 16 least minors 14 years of age or older. Other 17 minors may also be considered mature based upon the 18 evaluation of a parent and the physician. The more 19 mature the individual, the greater the weight to be 20 given to his or her opinion. So that basically 21 what you're trying to do, and I think rightly so, 22 is to balance the chronological age with 127 1 psychological age. But I think you need to -- I 2 think it's not helpful in a letter like this to 3 just leave it as vague as it will depend upon the 4 maturity of the individual as evaluated by whom. 5 All right. So, I mean, I think if you had 6 some kind of benchmark age, chronological age, that 7 could be -- I mean, you could have somebody who is 8 14 who is a seven-year-old in terms of abilities; 9 right? But, I mean, I think what you want to have 10 is a sort of a benchmark age like 14, you know, a 11 14-year-old was just convicted of murder; right? 12 And sentenced to 28 years; right? So the thing is, 13 I mean, I think that there is -- and you might want 14 to have a benchmark age and then also say, with the 15 proviso that, you know, younger children might be 16 mature enough and children of 14 or above might not 17 be mature enough. Something like that. 18 DR. FLEISCHMAN: May I clarify. You know, 19 based on that California statement which tracks the 20 New York State law somewhat, you're not suggesting 21 that parental -- that we talk to parents about 22 whether they think in this case -- 128 1 DR. DORFF: No. No. 2 DR. FLEISCHMAN: -- the child is mature? 3 DR. DORFF: No. This was -- I'm sorry, 4 that's right, this is only in regard to withdrawal 5 -- 6 [Simultaneous conversation.] 7 DR. FLEISCHMAN: Okay. But we're not -- 8 so there needs to be a process of determining the 9 maturity or capacity of the youngster, but it 10 doesn't involve a parent in that regard? 11 DR. DORFF: That's correct. That's 12 exactly right. 13 The second suggestion that I have is this, 14 toward the end you have in bold print, on the last 15 page, I think, finally, NHRPAC strongly urges the 16 development of a guidance for dissemination of IRB 17 that will explain the use of this section to 18 provide examples of procedural safeguards to 19 implement the part of the Section 408 -- do you see 20 that -- that requires appropriate mechanisms for 21 protecting the children. But you give such 22 safeguards. 129 1 Two pages earlier the last paragraph is in 2 bold. "In addition IRBs" -- but the sentence just 3 before that says, "Such safeguards might include an 4 individual, independent, or research team available 5 to counsel. They had a lesson to monitor the 6 consent process and provide ongoing independent 7 monitoring as appropriate." So why be bashful at 8 the end? Right? 9 In other words, it seems to me that what 10 we should be saying is there are such -- you know, 11 that we should have such procedural safeguards. 12 For example, this would be one way to do it. Not 13 the only way, probably, but at least here are some 14 -- just to show that it certainly is possible, you 15 know, and that here is a concrete suggestion as to 16 how it might be done. 17 And then my last point is just that you 18 mentioned earlier on in the document, before you 19 get to the conclusion that one of the things that 20 you want to do is to reconcile the FDA and HHS 21 requirements. I would make two points to that. 22 One is that you should include that point in a 130 1 conclusion just so that people don't lose sight of 2 the fact that that's another thing that is 3 motivating. And the other point that I would make 4 is that in the Federal Register materials that were 5 given to us and they come right after your document 6 in the book, the register itself -- the Government 7 itself wants to do that. I'm on page 20591. Under 8 "II. Highlights of the Interim Rule," second 9 paragraph, second sentence, the paragraph begins 10 "FDA is adopting HHS subpart D as directed by 11 Congress with only those changes necessary do to 12 the differences in FDA -- authority, the agency is 13 aware that dissimilar or inconsistent federal 14 requirements governing pediatric protection could 15 be burdensome to institutions, IRBs, in the process 16 of clinical investigation." 17 So the government itself is on record that 18 this is a concern of the government. And so what 19 you are trying to do is to say, well, if it's a 20 concern, then do something about it. 21 CHAIRPERSON MARSHALL: Thank you very 22 much, Elliot. I have Adil, Jonathan, Judy. 131 1 DR. SHAMOO: Alan, I'm troubled by this. 2 And the reason is as follows: These children 3 mostly likely will not be the children of this 4 committee or even the audience. They will be 5 children of the poor, the drug addicts, the 6 uneducated, and therefore we are establishing a 7 mechanism by which we could constrict their 8 children for research purpose not necessarily for 9 health care, it's research purpose. And that's how 10 it is going to be seen by the outside people. 11 Having said that, there is a point by 12 which government interests or the state interests 13 overtakes the family's interest in health care. 14 That's much more understandable. But this is for 15 research. And all the safeguards you have done, 16 and the safeguards that's been used previously are 17 based on the same research institution who has an 18 interest in increasing the number of their human 19 subject. As we have said before, prior to this 20 discussion on conflict of interest, there is an 21 inherent conflict of interest in the institution 22 that is the investigator wants 50 to 100 children. 132 1 The institution wants this money for this research, 2 there is a built in. And in your guidance it says 3 such safeguards might include that individual. 4 That disturbs me, "might include that individual" 5 why it should not be "should include an individual 6 who is outside the institution which provides an 7 independent objective judgment on whether this 8 drastic step of taking over those children for 9 research purposes for the general interest of the 10 public at large and the child her or himself. 11 DR. FLEISCHMAN: I think using "should" 12 rather than "might" if Professor Dorff agrees -- 13 [Laughter.] 14 DR. FLEISCHMAN: -- would be a -- you 15 know, I think would be totally appropriate. 16 We were soft here because we really were 17 holding out language toward the guidance. You 18 know, this letter is to the FDA, it is the working 19 group's hope that we will develop a guidance, we'll 20 get to that shortly. And that is where we were 21 going to be a bit more assertive in our language, 22 but I'm perfectly comfortable with "should" rather 133 1 than "might" in this language because I believe 2 that they should. 3 CHAIRPERSON MARSHALL: Jonathan and then 4 Judy. 5 DR. MORENO: First I want to subscribe to 6 Adil's suggestion. I do think we are potentially 7 on the horns of the classic double-agent dilemma 8 here. I am thinking though in the context of this 9 discussion I'm remembering a presentation I made to 10 a group a few years ago in New York that included a 11 number of advocates for homeless adolescents in 12 which I and our friend Jeff Bluestein argued that 13 there should be a high level of protection, a 14 greater level of protection for these young people 15 in research than might be required of the kinds of 16 kids who are parented by many of us in this room. 17 And one of the advocates, more than one, 18 actually, stood up after my presentation and said, 19 "you've got it exactly backwards. These young 20 people are very often much more" -- to use the 21 language that she used -- "street smart, much more 22 skeptical, much more careful about what they get 134 1 into than your kids would likely to be who have had 2 a good experience with authority figures." So I 3 simply put that on the table as kind of an 4 interesting -- it changed my perception of what 5 many of these kids are about. 6 My question that I have for anyone who can 7 tell me, since I also have only recently been 8 enlightened as a former IRB member about the FDA -- 9 the difference between the FDA and the common rule 10 on this is whether there is in parts 50 and 56 any 11 exception for adolescents whose parents are not 12 reasonably available, for example, and whether 13 authority for those adolescents to participate in 14 research can be achieved, for example, through 15 permission by a legal guardian. Or is that 16 unexceptional. 17 DR. FLEISCHMAN: Legal and authorized 18 guardians, I don't think there's a problem here. 19 Their problem, as I understand it and if our FDA 20 person is here who would like to comment -- she's 21 not. Okay. 22 Or one of the attorneys in the room more 135 1 knowledgeable than I on this, but my understanding 2 is their belief that not reasonably available -- 3 DR. MORENO: Would not cut it. 4 DR. FLEISCHMAN: -- would not cut it. If 5 they were a legal guardian, that's perfectly fine. 6 And they come to this based on the issue -- the 7 general issue of whether the law respects the 8 mature minor doctrine. And I think that's open to 9 interpretation. And I think they interpreted it 10 one way and we're asking them to change their mind. 11 DR. MORENO: May I just add one thing that 12 if it's not already obvious, some of the kids in 13 this population may suffer from conditions that 14 would not be prevalent in other kids. And 15 therefore, there may be special reason to attempt 16 to get them to be part of a research project, 17 understanding always the dilemma that Adil has 18 identified. 19 CHAIRPERSON MARSHALL: Thank you, 20 Jonathan. I have Judy and then Greg. 21 DR. SIEGEL: Both of my comments have to 22 do with being clear in this document and I think 136 1 we've talked about a definition of "mature" which 2 clearly I have no way to assess from this document 3 what our thoughts on the definition of "mature" 4 would be. So I agree, we need that. I also think 5 we need, in the part of this bolded statement that 6 deals with when the conflict between HHS and FDA 7 would occur, to be clear on the example given. I 8 don't actually think the example given is in itself 9 correct. You can do trials that include drugs that 10 would not be subject to FDA rules. And so -- I'm 11 saying you can. There are examples. 12 And so I think in the piece here where we 13 are actually comparing the trial where at that 14 moment you would have a conflict within the trial, 15 we just need to be a little bit more clear and also 16 be clear on where we would always have to invoke 17 the FDA ruling on this. 18 DR. MORENO: You're thinking about a non- 19 phase trial? 20 DR. SIEGEL: Yes. Sure. A drug that's 21 been approved that someone is using and looking at 22 a different indication. Anything that is not, 137 1 quote, going to be used for a regulatory approval 2 of some sort would fall out of this. 3 DR. FLEISCHMAN: Or a technique or a drug 4 -- 5 DR. SIEGEL: Yes. So for this, if we're 6 going to include it, I think we should have an 7 example of where HHS would be the only rule to 8 invoke or FDA would be the only rule to invoke and 9 when you have the conflict, which is where we 10 actually want to deal. But further, the question 11 is, do we actually now say, under HHS, if you do an 12 HHS rule study you have this decision to make and 13 if you do an FDA, you have this decision to make, 14 which we will discuss at several points today. We 15 have conflicting rulings and at one point are we 16 going to at least suggest that they are going to be 17 brought together somewhere. 18 CHAIRPERSON MARSHALL: Thank you. Greg. 19 DR. KOSKI: Just one comment and then I 20 would ask the committee to sort of opine on 21 something. I wanted to just sort of respond 22 briefly to a comment that Adil was making with 138 1 respect to conflicts of interest among 2 institutional review boards in an institution. I 3 think we've come to realize that while there are 4 certainly instances where an institutionally 5 appointed board may be in a position whereby they 6 may not be serving the best interests. There could 7 be pressure to somehow influence by the interests 8 of the institution that does occur and it's 9 unacceptable, so that needs to be fixed. 10 But on the other hand, I don't think we 11 should lose sight of the fact that there are many 12 institutions that have made a very real and serious 13 commitment to protection of human subjects and 14 indeed the interests of the institution are best 15 served by having an institutional review board that 16 takes that seriously as well. 17 So it's kind of like the whole conflicts 18 of interest thing, you know, it depends upon where 19 you happen to be standing. I don't think we want 20 to indict all institutional review boards based at 21 institutions as somehow being, you know, corrupt. 22 I think what we need to do is make sure that all 139 1 institutional review boards are appropriately 2 constituted and positioned so that they are free to 3 exercise autonomous decisionmaking to protect human 4 subjects. It's just an aside remark to get that 5 out. 6 The point that I wanted though to ask the 7 committee about, we started out with Alan saying, 8 "might" and then Adil said, "should"; well, what 9 about "must"? I mean, is this -- 10 [Laughter.] 11 DR. KOSKI: And, you know, I just would 12 sort of push the envelope, as long as we are 13 exploring all of this, as I said, if this is an 14 area in which there is sufficient concern, and it's 15 sufficiently complicated that we, again, need to 16 make sure that everyone is doing it the same way. 17 Again, if we were to change either what's in the 18 current, you know, FDA regulation or in the -- it 19 is going to be a regulatory change. We are going 20 to do something we might as well do it right the 21 first time and not have to go back. So I just ask 22 you to explore that. 140 1 DR. FLEISCHMAN: The working group I don't 2 think would have any problem with "must," but what 3 I learned this morning was that "must" is based in 4 regulation so we could recommend that a new 5 regulation be created with a "must" but even before 6 that occurs, we would recommend a "should". 7 DR. KORNETSKY: I would also be concerned 8 if we do recommend it as a "must" then we are 9 developing something that's different than HHS. 10 So, if we're saying "must" for FDA, that we must 11 have an advocate, that's not something that is 12 embedded in HHS regulations, so it may be 13 incongruous there. 14 DR. FLEISCHMAN: 408(c) has been used in 15 far less onerous research processes than drug 16 trials. It has been used with populations who have 17 been allowed to get clinical care and have minimal 18 risk questionnaires around sexually transmitted 19 diseases, other kinds of behaviors and in that 20 regard the level of protection and the procedural 21 safeguards need to be titrated to the level of risk 22 to the individual subjects. So we would certainly 141 1 -- I think the working group would agree on a 2 "must" for anything that was FDA-related clinical 3 trials of drugs that were still in the regulatory 4 structure. On the other hand, the beauty of the 5 language of 408(c) now allows the IRB to be 6 flexible enough to develop protocol specific 7 procedural safeguards and we referenced the Journal 8 of Adolescent Medicine work of their -- of the 9 Society for Adolescent Medicine group a few years 10 back that reviewed this question and tried hard to 11 get this concept across of the level of protection 12 and the procedural safeguards being consistent with 13 the level of risk to the subjects when parental 14 permission is being waived. 15 So we need to clarify all of that. If we 16 were going to put a "must" in, we would have to be 17 very clear that we were suggesting that in the most 18 serious concern studies. 19 CHAIRPERSON MARSHALL: Greg, I think, 20 would like to, while we're talking about hortatory 21 language would like to weigh in. 22 DR. KOSKI: Actually, Alan just made the 142 1 point that I was going to make that, you know, if 2 there is a "must" a "must" can be appropriately 3 framed with respect to -- and we see this in the 4 way Sections 4, 5, 6, and 7 are already put in 5 there, that there's a graduated consideration of 6 risk and benefit and that certain things are only 7 required when a determination has been made that, 8 and in that case there's a specific requirement to 9 go above and beyond and it matches the level of 10 risks with the level of protection and all. So I 11 think we're saying the same thing. 12 MR. BARNES: It seems to me just as a 13 formal matter, Alan, that really what we should be 14 saying to the FDA in these regards is we are asking 15 or recommending that they take an aggressive 16 interpretation of their own authority under their 17 existing regulation to achieve the objective that 18 we want, or if they don't want to do that, we're 19 suggesting that they change their regulations in 20 50.20 to be consistent with the common rule. And 21 so that is really the -- you know, in terms of the 22 formal recommendation, I think that's what we're 143 1 making to the FDA. 2 CHAIRPERSON MARSHALL: Let me -- I haven't 3 seen hands come up from the committee and in 4 thinking about time, what I would like to do is 5 maybe continue this discussion until noon and then 6 give Alan time to move on to discuss other working 7 group matters, if he so chooses. I know that Dr. 8 Lepay is here. David, if you would, at any point, 9 like to have the floor, it is yours. 10 DR. LEPAY: Let me make a clarification 11 here. I think several sections of this rule were 12 pointed out in its preamble. Certainly we do 13 recognize some of the differences that exist. Our 14 goal was, of course, to eliminate these differences 15 to the extent possible. Now, what we are talking 16 about -- here, again, I'm not a lawyer, and I don't 17 know if I have any representation here behind me 18 from FDA's legal end. So I would want to be very 19 careful how I phrase this. 20 MR. BARNES: You want to say nothing. 21 [Laughter.] 22 DR. LEPAY: Our understanding of the 144 1 reason the language was proposed as it was, was not 2 based on current FDA regulations, but rather an 3 interpretation of the Food, Drug and Cosmetic Act 4 which underlies FDA's regulations. So, FDA alone 5 is not in a position necessarily to be able to make 6 the kind of changes that would support complete 7 identity of these two regulations in these areas. 8 Ultimately, again, unless we are interpreting this 9 incorrectly, the changes would have to be made at 10 the level of the FD&C Act and legislation to that 11 effect. Again, speaking as a non-lawyer here. 12 I think as we start to talk down that 13 line, one of the considerations here, and 14 particularly if we go the route or at least the 15 recommendation is to go the route toward changes in 16 legislative language. We have to be very careful 17 how we go about doing that because basically the 18 read of FDA's current -- the FD&C Act in these 19 areas is in fact one that FDA is not able to 20 provide IRBs with the authority to waive informed 21 consent. 22 So, indeed, if we are starting to move 145 1 down this route, what it can effectively do in 2 changing the law that governs these particular 3 provisions, we have to make sure that we are not in 4 fact opening up a whole situation where the 5 informed consent requirements under the law are 6 lessened to be much broader than what we are 7 talking about here in one provision of one 8 regulation. 9 So I think this is really what the 10 committee does need to take into account and to 11 deliberate on if the recommendation is indeed that 12 this is an important point and needs to move 13 forward toward legislative changes to accommodate 14 it. I think it's going to be a multi-step system 15 where we are going to have to see where that 16 legislation will go and how to prevent it from 17 otherwise reducing the protections that currently 18 exist in the law for human subject protection. 19 CHAIRPERSON MARSHALL: Thank you very much 20 for clarifying that. And I would also like to 21 thank you and the FDA for allowing us to make these 22 comments after the fact in terms of your time 146 1 frame. We are very much appreciative of that. 2 Alan. 3 DR. FLEISCHMAN: And I do appreciate your 4 clarifying that. The working group would argue, 5 again, with no lawyers behind me either, that we 6 are not waiving informed consent. And that is the 7 substance of our argument as to why we believe the 8 FDA might be able to interpret and I loved Mark's 9 language, and we will try to use that language, but 10 we believe that the adolescent, him or herself who 11 is mature and who has the capacity, is giving 12 informed consent, not assent, and that we are not 13 waiving informed consent in this regard. That's an 14 important part of the ethical underpinning of this 15 section. It isn't that no one is giving informed 16 consent, it's that we are respecting the young 17 person as a person who has the capacity and 18 therefore we give him the authority to give the 19 informed consent. 20 Now, that may have no legal standing 21 whatsoever in the Food, Drug and Cosmetic Act, but 22 we hope it would. 147 1 CHAIRPERSON MARSHALL: Thank you. And now 2 let me ask if there are ex-officio members of the 3 committee who would like -- any ex-officio? 4 [No response.] 5 CHAIRPERSON MARSHALL: Then let me just 6 open the floor, and I would like to recognize Vera 7 who is a member of the working group and has given 8 us a written dissent that we should put on the 9 table and discuss. Thank you, Vera. 10 DR. SHARAV: Thank you. Even from the 11 discussion just now, it has become apparent that 12 terms have no real definitions. For example, 13 informed consent according to the law as Dr. Lepay 14 again reminded us, is very specific. Only 15 competent adults, under the law, can give informed 16 consent. 17 The law also speaks of children. There is 18 no division right now between children and 19 adolescents. And all children can only give 20 assent, legally. 21 The definition or the supposition that 22 abused and neglected children would be better 148 1 served by assuming the responsibility -- the adult 2 responsibility on their shoulders by waiving the 3 parental involvement. 4 Now, I would like to know what evidence 5 there is that that is so. First of all, who 6 decides who is an abused and a neglected child? 7 Again, there are legal stipulations and someone 8 else will talk about it; Howard Fishman is an 9 expert on this. But just to lay the ground, there 10 are definitions and the committee is really either 11 unaware of those very specific requirements before 12 a child is adjudicated as an abused child and 13 someone else is assigned to make decisions on their 14 behalf. That is very different from what is 15 happening here. 16 The other area that I would like to 17 mention that was mentioned before about "should," 18 "must," "might; there are some assumptions being 19 made about the current level of safeguards in human 20 subject research, both adult and children. 21 And those assumptions in light of the real 22 world, and should I list all these scandals that 149 1 we've had in the last three years, I think everyone 2 knows it, but the big elephant is not in the room. 3 The question I have, why is there such a rush to 4 accommodate research by diminishing the protections 5 that children now have? Those protections restrict 6 access to them. That's the one safety that they've 7 had until now, that there had to be very strong 8 justification for using children in experimental 9 research. 10 It was, again, affirmed by the Radiation 11 Advisory Commission that has a very strong chapter 12 about why children need particular protections, and 13 I really do find it almost offensive to call it 14 "added protection" when in fact we are reducing 15 them by assuming a whole lot of things which have 16 not been proven. 17 I think that for the government to enter 18 into the family -- the parent/child relationship 19 and in some manner diminish it without having very 20 strong justification, that the child first of all 21 needs that, or that he will better off after. 22 There are victims in research. We all know that 150 1 research involves risks. What happens when a child 2 is harmed, one that the parent was not involved? 3 Do you bring back the parent? Who will take care 4 of that child? Who will worry about him once he's 5 finished with research and he's harmed? Or, just 6 the fact that he's now on his own. There has been 7 a breach in that parent/child relationship which 8 was initiated by the government. I think that's a 9 very heavy load for this panel. I really do. 10 CHAIRPERSON MARSHALL: Thank you, Vera. I 11 sit on this working group as well. And I would 12 like to respond to your comments by saying that the 13 very sorts of research that we're talking about and 14 that I think have been very clearly articulated are 15 the sorts of research that would aim to prevent 16 harm to children to include children who are in a 17 certain situation who may not have access to 18 research, but whose situations need to be 19 understood and learned about so that we can care 20 for those children in a better way. 21 So, I understand your sense of outrage and 22 I think all of us have it. In particular 151 1 situations it does our consciences credit, but it 2 is not always a service in terms of what we are 3 trying to achieve professionally as a committee. 4 So, I can't agree with you. I think 5 there's a little bit of disingenuity in your 6 remarks. And I'll stop there and maybe ask if 7 anyone else has comments that they would like to 8 make. Felice. 9 DR. F. LEVINE: I think as a member of the 10 working group, I think, Mary Faith, at least as I 11 would see it and heard it and feel it as a 12 contributor, better captures the spirit of the 13 working group, and that is to -- for a particular 14 -- I'll say somewhat narrow class of adolescents to 15 provide than the opportunity to be subjects where 16 they otherwise would not have that opportunity and 17 where we cannot, therefore, help them absent their 18 having the capacity to participate. And this is 19 not so classed-based. 20 As I said on the phone, if anyone would 21 like to take a field trip, I can take you to some 22 of the best neighborhoods in town than we might 152 1 like to think. I think there's a lot of 2 sociological stereotyping about this as if we are 3 talking about person who couldn't possibly be the 4 adolescents of people around this table and were 5 not, as we know. 6 CHAIRPERSON MARSHALL: Thank you. Mark. 7 MR. BARNES: I'm not a member of the 8 working group, but I wanted to offer one example 9 which may actually refine the controversy. Alan 10 had used the example, I think, in his draft report 11 or draft letter and also here during his remarks of 12 the adolescent who might want to be enrolled in an 13 AIDS/HIV drug trial because those trials in fact 14 have been -- many of them have been -- especially 15 with the proteus inhibitors have been enormously 16 successful. And the trials were even aborted in 17 the middle of them because they were thought that 18 the prospect of success was huge and in fact the 19 success was huge. In some cases leading people to 20 say or to regard the effect of the proteus 21 inhibitors as what's called the "Lazarus Syndrome." 22 So, in fact, it was not even a marginal gain in 153 1 health, it was a huge gain in health for those 2 people that participated in the trial at an early 3 stage. 4 But I think there may be an even better 5 example, Alan, which is -- it's an earlier example 6 in AIDS/HIV of NIH trial O76 which involved the 7 administration of AZT as adavudine to pregnant 8 women in various dosages in order to prevent 9 infection of the fetus of the child when he or she 10 was born. 11 And in regard to maternity services, it's 12 quite clear in the law that adolescents who are 13 mature have the right to consent to their own care 14 regardless of what their parents may or may not 15 say. They have the right to seek reproductive 16 counseling, they have the right to seek abortion 17 services if they so desire. This is a principal 18 that's enshrined in most of the either state 19 statutory laws or respected by state courts when 20 they've interpreted state constitutions. And, in 21 fact, the O76 trial was really about maternal care. 22 It was not about care necessarily of the mom, 154 1 although that was important too, but it was also 2 about her decisionmaking about the safety of her 3 child or child to be. 4 So, in fact, the O76 trial itself was 5 aborted because the early results of the trial were 6 so positive in terms of making it clear that the 7 administration of AZT, at least in limited dosages 8 during pregnancy was, in fact, going to protect 9 these children -- the children to be born. 10 So, in fact, I like that example perhaps 11 better than simply the proteus inhibitor example 12 because it relies on an underlying category of 13 girls, of females, women, young women -- who knows 14 what to say these days -- 15 [Laughter.] 16 MR. BARNES: -- whatever. 17 [Laughter.] 18 MR. BARNES: But I like that example 19 because it is a category of decisionmaking which is 20 historically reserved to the less than 18-year-old. 21 And yet it was a situation in which the enrollment 22 in the trial led very directly to positive health 155 1 consequences. 2 DR. FLEISCHMAN: Mark, I would strongly 3 urge us not to use that example. I know that trial 4 extremely well. Those young women who were less 5 than 18 and who were pregnant and who were 6 enrolled, were enrolled as emancipated minors which 7 is a different category than we are talking about. 8 Because of their pregnancy, they were felt to have 9 the same rights and legal standing as adults. And 10 this is a different group. I wouldn't want to base 11 our argument on what I think are a legally adult 12 standing -- that the young women in O76 had. I 13 don't think any IRB used 408(c) in that regard. 14 I think there were other issues about O76 15 concerning paternal consent and other things that 16 we could perhaps talk about at some time, but that 17 -- and with all due respect, I think that example 18 is not the one that I would share with the FDA 19 because I think they would then blow away all the 20 other mature minor issues. And I think we need to 21 define what we mean by "mature minor" very 22 carefully, distinguish it from the emancipated 156 1 minor which are those youngsters who are less than 2 18, independently contributing to our society 3 through work or having been parents or are pregnant 4 which is my understanding of that distinction. And 5 I would just respectfully suggest we not go down 6 that road. 7 CHAIRPERSON MARSHALL: Abbey. 8 MS. MEYERS: Well, I just want to say that 9 part of the whole bioethics discussion is respect 10 for persons, and we need to respect the wishes of 11 an adolescent not to tell their parents something, 12 just as no parent has the right to have access to 13 the psychiatric records of their child. There are 14 other issues that children don't want to talk to 15 their parents about and they should have that 16 right. So I don't think that we should eliminate 17 this whole class of people just because they don't 18 want their parents to know something. 19 CHAIRPERSON MARSHALL: Please, if you 20 could use the mike and identify yourself. 21 DR. FISHMAN: Hi. My name is Howard 22 Fishman. For the past seven years, and it goes 157 1 back much longer, I have been consulting on and 2 acting as an expert witness in child abuse cases. 3 I've been qualified as an expert in 13 4 jurisdictions. There are some fundamental kinds of 5 issues that are raised when people say that someone 6 has been disingenuous. That's problematic for me. 7 Because what has been utterly and totally ignored 8 are the rights of parents, and what I have referred 9 to as this concept of in loco parentis running 10 amok. 11 People who propose to replace parents with 12 their infinite wisdom perhaps ought to be called 13 upon to replace the so-called "research subjects" 14 with their own children. It's very easy to talk 15 about what should happen to someone else's kids. 16 We were reassured a few minutes ago that 17 this is across the spectrum of socioeconomics, et 18 cetera. Wrong. There are 600,000 children in 19 state care in the United States. A larger 20 proportion than any other nation in the world. The 21 preponderant majority of those children have never 22 been physically harmed or sexually abused by their 158 1 parents. 2 Furthermore, nowhere in this document do I 3 see a definition of an abused or neglected child. 4 And I've heard five or six times, well, you know, 5 we really have to look at better definition. I 6 can't imagine how a position could have been 7 arrived at without those definitions. Legally 8 there is a definition. An abused or neglected 9 child is an individual who has been adjudicated as 10 abused or neglected in a court of law. 11 I hate to tell you, maybe FDA should be 12 aware, that even when a child has been adjudicated, 13 abused, or neglected, the state, the custodian, 14 does not have permission, may not proceed to 15 provide medical treatment to that child without 16 parental permission. Such a status is achieved 17 only when parental rights are terminated. 18 These are niceties that are somehow 19 ignored in all of this. But the fundamental issue 20 is the undermining and sabotaging of the American 21 family and of the American parent. And, again, 22 this issue of across the broad spectrum of 159 1 sociopolitical statuses, nonsense. 2 The vast majority of children in state 3 care are minorities. They are of the 4 socioeconomically marginalized populations. So, 5 I'll conclude with where I started. To the extent 6 that folks here would like to volunteer their own 7 children, they should feel free to just ignore the 8 parents of these other children who are far more 9 vulnerable, far more susceptible to coercion, to 10 manipulation, and to bribery. 11 When we find that the most prestigious 12 research institution in this country has been 13 assessed and found to evidence fundamental flaws in 14 its research protocols and ethics, and then we want 15 to blithely suggest, well, most IRBs are doing a 16 fine job. Please, folks, that's disingenuous. 17 CHAIRPERSON MARSHALL: I see a few hands 18 go up. I don't think that anyone on this committee 19 has made any blithe suggestions this morning. And 20 I won't speak for -- I am not a parent myself, so I 21 can't speak to that. But I would ask any other 22 committee member who may wish to do so. 160 1 But I also would like to remind us, and I 2 generally start the meeting this way, and I didn't 3 this morning for time purposes, and that is that 4 our remarks should be made in the spirit of 5 respect, they should be made in the most accurate 6 way possible, without sweeping generalizations, 7 without anecdote, and so I would hope to keep the 8 level of discourse -- I will keep the level of 9 discourse of this meeting at a high one in terms of 10 respectful interactions between individuals. 11 And when I sense that members of the 12 committee or members of audience are not treating 13 one another with that respect, then I will say so. 14 Dr. Koski, I see two hands -- Dr. Koski, Alan, and 15 then the two folks there on the front row. 16 DR. KOSKI: Thank you, Mary Faith. Just 17 very quickly, I found myself several times today in 18 sort of the position of shifting perspective a 19 little bit for the sake of fostering greater 20 communication. I find myself there once again. 21 I think there is a great deal of truth to 22 what Vera pointed out that there is a certain 161 1 presumption that, you know, there is, will be, I 2 would say, must be, an effective system for 3 protection of human subjects overall if we're going 4 to make what we do meaningful. And, so, clearly, 5 that's an area that, you know, we shall continue to 6 work in. 7 But, nevertheless, the perspective that 8 one brings to these discussions, okay, can in a 9 very substantive way sort of color what you see. 10 And if one starts with the presumption that all 11 research is being done by, you know, evil 12 entrepreneurial self-serving malevolent individuals 13 that want to harm people, then you come down sort 14 of on one side. I'm speaking now as an extreme, 15 whereas, if you, on the other hand were to believe 16 that none of those things were true, you might come 17 down on the other. The truth is, we have to 18 operate sort of in this -- more in the middle 19 region. Okay. And that's complicated. 20 I think that in my reading of what the 21 working group has done here, there is a genuine 22 belief that there's a need to address the concern 162 1 that some adolescents might be prevented 2 unnecessarily from participating in research and 3 thereby deprive them of what might be real benefits 4 toward understanding the conditions that affect 5 them and providing ways to help them. So I believe 6 it was in that spirit that many of these 7 recommendations were made. 8 At the same time, I think we can't lose 9 sight of the fact that there is a need for real 10 protections because there may be instances where, 11 again, people step out of that bound and begin to 12 try to be, you know, exploitative from what they 13 are doing. And so it's -- I think we've got to 14 consider, you know, both of these sort of views as 15 we go forward to make sure that any policy 16 recommendations or regulatory changes that might be 17 made will reflect that appropriate balance. 18 By the way, I have enrolled my own 19 children in research trials. 20 CHAIRPERSON MARSHALL: Elliot. 21 DR. DORFF: I think it's important to 22 understand that the background behind all of this 163 1 is a problem that we have in our own society in 2 understanding teenagers. 3 [Laughter.] 4 DR. DORFF: My kids are in their late 5 twenties and early thirties already, so I'm well 6 beyond that. I really understand it. No, I don't. 7 [Laughter.] 8 DR. DORFF: What I am recalling is a 9 lecture I once heard by an anthropologist who 10 compared what happens in America to what happened 11 in a particular South Sea Island where people are 12 children until age 15. At age 15 they have a 13 particular right, one for women and one for men. 14 And at the end of that right they are adults for 15 all intents and purposes. And they compared that 16 to what happened in the United States where you 17 become an adult for admission prices to movies and 18 for airlines at 12. You become an adult for 19 driving at 16. You become an adult for voting at 20 18, for alcohol at 21, and if you're a male, you're 21 not an adult for car insurance until you're 25. 22 Right? 164 1 So from 12 to 25 we have this gray area 2 where we don't really know, you know, what we're 3 supposed to say about people in that age group and 4 what responsibilities they can take on themselves, 5 and what kinds of decisions they should be able to 6 make for themselves. And, we as a society, are 7 facing this kind of thing in these cases recently 8 in a variety of different states having to do with 9 how you treat teenagers, do you put them into adult 10 courts, or do you put them into juvenile courts? 11 And for what purposes? 12 I mean, this kind of problem that we have 13 is a problem in law as well as a problem in terms 14 of how to treat these people. And I think that -- 15 well, in my own tradition it starts at 13 where you 16 have the right to make these kinds of decisions and 17 also the responsibility. 18 Now, that comes from a period long past 19 when life expectancy was less and all kinds of 20 other things were true. But you didn't go to 21 school until your mid-20s. But the thing is that 22 -- I mean, I think we have to understand that the 165 1 underlying reality to these problems that we're 2 having has to do with how we understand 3 adolescents. 4 My own feeling is that when you're talking 5 about what we're talking about, namely that, you 6 know, these kinds of trials, and I think Dr. Koski 7 -- Greg, is exactly right. I mean, we have to 8 presume the middle ground. We have to presume that 9 everybody involved in drug trials and conducting 10 them is not on the one hand a saint, but on the 11 other hand not necessarily a sinner either; but is 12 rather a normal human being with propensities for 13 both ends of the spectrum. 14 And what we want to do is make -- I mean, 15 what this letter wants to do and the reason why I 16 support it is because it enables people roughly 14 17 to 18 to become part of trials that may ultimately 18 be for their own benefit, and certainly will be for 19 benefit of others that are of that age. And to 20 recognize the fact that some people in that age 21 group certainly have the ability, and the 22 responsibility, to make these kinds of mature 166 1 decisions. 2 If they can drive a car at 16 and endanger 3 all the rest of us that way, and we have good 4 evidence of that, then on this kind of thing, I 5 mean, it seems to me that this is at least opening 6 the door for some of these people who choose to do 7 this, to do this recognizing that they've achieved 8 at least a certain level -- a necessary level of 9 maturity to be able to make that decision. 10 CHAIRPERSON MARSHALL: I'm sorry. Please 11 go ahead and then I have Gail and then I have 12 Jonathan. 13 MR. SUSKO: Hi. I'm Mike Susko, the 14 president of CRCR, Citizens for Responsible Care in 15 Research. I agree with the principle of dialogue 16 that we are really talking about tension between, 17 in some sense, too noble a cause as one is, can we 18 do some research that really benefits people? 19 I was talking to the head of the Pain 20 Clinic at Hopkins and there is a nobility in trying 21 to stop pain and trying different things with that 22 problem that's not fully solved. On the other hand 167 1 there is the issue of the protection of the 2 research subject and truly informed consent about 3 the risks and there's nobility in people who tried 4 to defend that cause. So there really is attention 5 here. 6 I think, though, my view would be we might 7 tend to err on the side of protection. And the 8 Nuremberg Code sort of said, informed consent was 9 the bottom line. That's got to be the bedrock 10 principle. We can't gain, you know, other advances 11 at that risk because then you run into, you know, a 12 lot of problems. And so the difficulty of informed 13 consent intrigues me. 14 I was talking to a pathologist and she 15 said, "well, I would never enter into a new drug 16 study because I know there's a percentage with 17 adverse effects and some might die." Nor would she 18 put her children in. So here is a mature woman who 19 knows the field, who just wouldn't do a certain 20 type of study. And then we are going to say, well, 21 a mature adolescent, you know, who doesn't know a 22 lot of the hard science and so forth, is able to 168 1 make some sort of decision. 2 And I reflect back on the recent death in 3 my home town of the Baltimore woman. And I looked 4 at the consent form about the asthma inducing agent 5 there and the title of the study was "Relaxation" 6 it had the word "relaxation" in it. They said you 7 might get drowsy if you try to stand up. Just when 8 you read that whole consent form, I mean, you had 9 to be somewhat expert to figure out what was really 10 going on that there might be a high risk. And I 11 just think of a mature adolescent trying to grapple 12 with some consent form and then make, you know, 13 really informed consent decision. It seems like 14 there should be a type of advocate for the child if 15 you're going to have any type of waiver. A devil's 16 advocate or maybe a children's advocate, we would 17 call it. Somebody who would help the child make 18 sense of what is going on in here and not just the 19 people who have a vested interest in the research, 20 a neutral party would be a suggestion. Thanks. 21 CHAIRPERSON MARSHALL: Thank you very 22 much, Mike. And I think, you know, as we were -- 169 1 as Alan mentioned, we feel as those procedural 2 safeguards, not only up front in terms of consent, 3 and support there, but ongoing monitoring is 4 something that we will include in our letter in the 5 "should" category and that we may exorge the FDA or 6 others, that should they change the regulations in 7 the future that then the "must" category would be 8 entered in terms of continued oversight. 9 MR. SUSKO: When we are talking about 10 ethical principles, there's a principle of 11 distributive justice here too. In the American 12 Academy of Pediatrics in 1995, I had a committee on 13 drugs combined with a committee on bioethics who 14 published an article in pediatrics saying that it's 15 actually unethical not to do studies in children. 16 And this is a very special group of children that 17 Alan is pointing out that need also to benefit from 18 that principle of distributed justice. It's wrong 19 to leave them out. 20 You're trying to craft a way within all 21 legal bounds to include them in research because 22 they can get permission for themselves to be 170 1 treated as children. There may be a very important 2 drug that they need that it would be ironic that 3 they could not receive and it would be in 4 contravention to these beautiful ethical principles 5 espoused by the American Academy of Pediatrics. So 6 I do feel strongly about that. 7 I would also like to add that a child -- a 8 male child between 21 and 25 cannot rent a car. 9 That's very interesting too. So there are these 10 ethical principles that are definitely in 11 contravention with one another. 12 But I would say that Vera has a good point 13 and also Dr. Fishbein, I believe, because we do 14 have to pay attention to the legalities. And maybe 15 there are not enough lawyers in this group. 16 Because there are definitions in law that we have 17 to pay attention to. I think that was a good 18 point. But another point was about the distant 19 ingenuity that is going on around here. 20 On page 4 of your rebuttal, you mention 21 the "child abuse industry." And I don't know if 22 anybody would classify themselves as working in the 171 1 "child abuse industry". I'm not sure that's a good 2 term. 3 MR. BARNES: Could I say, that's the only 4 time I've ever heard a doctor say that there aren't 5 enough lawyers in the room. 6 [Laughter.] 7 CHAIRPERSON MARSHALL: I have Jonathan, 8 Roger, Adil, and Greg. 9 DR. MORENO: Thank you. I guess I must be 10 a lot younger than Elliot because my kids are 15 11 and 11 and a half. And at the risk of committing 12 what I'm sure Felice would observe is the fallacy 13 of assertion by hypothesis because I'm not in this 14 situation, if either of my kids were in the 15 situation described on page 2 of Alan's report, 16 then I would hope that they would -- and if they 17 didn't feel they could confide in me or my wife, I 18 would certainly hope that they could feel able to 19 enter a clinical trial that could be beneficial to 20 them. 21 But that leads me to a concern that I do 22 have that we are all familiar with, with respect to 172 1 the current regulations, namely the meaning and 2 interpretation of beneficial. And I do think, 3 Alan, that we need to flesh that out a bit more, 4 particularly with respect to this population. At 5 least we need, I think, to have some more 6 procedural understanding about how benefit is going 7 to be understood, how those conclusions would be 8 reached, and perhaps even some guidance about what 9 would not be considered to be beneficial. 10 For example, would a placebo controlled 11 study be considered -- I hear Bob Levine shouting 12 in my ear. So I think that perhaps that phrase 13 carries the greatest burden in this set of 14 recommendations. I do think we need to perhaps 15 give more attention to how that conclusion is going 16 to be reached. I'm not sure I would want either of 17 my kids to be in a study that was not potentially 18 beneficial if they were in the circumstances 19 described. 20 And I'm not sure I would have utter 21 confidence in just anyone making that determination 22 without a little more public guidance about what 173 1 the criteria might be. 2 CHAIRPERSON MARSHALL: Alan. 3 DR. FLEISCHMAN: I'm jumping the queue to 4 respond to Jonathan and perhaps I'll respond to Dr. 5 Fishman as well. I think this letter can't carry 6 too much freight here. I'm quite in favor of our 7 trying to clarify through guidance the concepts of 8 beneficial. And if we have the opportunity and the 9 working group will report its intention to do that. 10 It is extremely difficult for this simple letter to 11 carry too much freight. 12 I would argue that IRBs ought to make this 13 determination very carefully. This is not 14 something that IRBs ought to suggest they embark 15 upon wholesale. These are very specific kinds of 16 protocols. The reason we gave the example was 17 because these were protocols that had tremendously 18 promising results in adults, but still hadn't yet 19 been completed and the investigators wished to 20 enroll the youngsters because this was another 21 cohort who could directly potentially benefit. 22 So, how we would frame that without 174 1 knowing the case-by-case basis what kind of 2 language we could put into something like this, 3 except to exhort the IRBs, to be very careful, to 4 be very circumspect about what kinds of protocols 5 they would allow this to be in, I'm not certain and 6 that's what could be troubling. I could consider a 7 placebo controlled trial. I could. You know, I 8 could hypothesize, a placebo controlled trial in a 9 disease for which there was no therapeutic 10 intervention that had a one-year life expectancy 11 with some suggested hope in adults before we had 12 any therapies that were standard. I might consider 13 an adolescent placebo control trial under these 14 circumstances. So, you know, I don't want to get 15 into that level of detail, but I don't know how to 16 use this document to do that work. That would be 17 my response to Jonathan. Although, I would exhort 18 IRBs to be very careful, thoughtful and give the 19 idea that there was some hoped-for benefit knowing 20 full well, as Adil points out, that even in the 21 best of intended studies, there may be toxicities, 22 there may be risks, there may be unknown problems. 175 1 That's why we're doing the research. 2 DR. MORENO: Could I just have a quick 3 follow-up. One, I acknowledge the difficulty of 4 loading the document with answers that we may not 5 be able to articulate at this point, but one 6 example of something we might want to consider as 7 part of the guidance would be that IRB should do 8 what they have the authority to do, mainly to bring 9 in consultants who are expert in the condition that 10 applies to these kids, which might not otherwise be 11 the case. 12 MR. BARNES: May I go back to Dr. 13 Fishman's comment, which I did appreciate, and I do 14 think that Dr. Fishman's definitions are clear and 15 I think correct. But let me remind the committee 16 that we're not talking about children primarily 17 here in this case who have been determined to be 18 abused and neglected, nor are we talking about 19 children or their parents who have gone through the 20 process of termination of parental rights. What we 21 are talking about are a group of youngsters for 22 whom abuse might occur. 176 1 We don't have absolute certainty. But 2 they have suggested that their families might 3 respond to the truth telling with responses that 4 would be very hurtful to them. And I've had the 5 consequences speaking to such youngsters who have 6 convinced me, certainly, that they would be thrown 7 out of their homes where they're going every night 8 now and getting good meals and getting housing, 9 that they might be abused or worse, in revealing 10 their diagnoses to their families, and they are not 11 neglected or abused, they haven't been adjudicated 12 as neglected and abused, their parents' rights 13 haven't been terminated, nor does this approach 14 attempt to do any of that work. And in those cases 15 in which children are abused and neglected, then 16 the pediatricians have the responsibility to go 17 down that path. But that is not what we are 18 talking about here and I think it's important that 19 the committee understand that we're not speaking 20 merely about -- I use the word "merely" in quotes, 21 "merely" about abused and neglected children, but 22 we are speaking about specific adolescents who are 177 1 mature and who have serious illnesses for whom they 2 don't wish, as Abbey has pointed out, the 3 appearance to be informed. 4 CHAIRPERSON MARSHALL: I have Roger, Adil, 5 Vera, and then Greg, and I'm going to stop there 6 procedurally so that we can come to closure on 7 this. 8 MR. CORTESI: My only question is, how 9 often is it necessary to use as subjects, children 10 who will or adolescents who will not get their 11 parents' permission. I mean, are we talking about 12 a widespread problem or are we talking about 13 something that comes up once in a blue moon? 14 DR. FLEISCHMAN: I don't know about blue 15 moons, but it's not a widespread problem, it's a 16 very unusual problem. But it is an important 17 problem. Because there is good reason to believe 18 that if you exclude these youngsters you will not 19 be getting the population that you need often to 20 answer the questions you're asking. And that's 21 very important to all youngsters to have the 22 appropriate population for whom the therapeutic 178 1 intervention will likely be used. And, once it is 2 standard treatment, then it can be used for 3 youngsters without parental permission in clinical 4 use based on the youngsters coming forward and 5 asking clinician to treat them and we allow in each 6 of our states for that to happen. But we would 7 never have done the research to assure that those 8 children were safe. 9 So, it is rare, and that's why I prefaced 10 this whole discussion by saying this is not the 11 most important issue. The working group will 12 discuss in its tenure, but it is an important 13 timely issue. 14 CHAIRPERSON MARSHALL: I have Adil then 15 Vera. 16 DR. SHAMOO: This is specifically in 17 answer to Dr. Koski's comment because it's been 18 twice made. And that is whether the IRB members or 19 IRBs whether they're 100 percent evil or 100 20 percent good or zero percent evil, however you say 21 it. I for one have stated publicly and orally that 22 I think the overwhelming majority of researchers 179 1 and IRB members are noble people. That's really 2 not the question. 3 The question is, what percent? We know 4 it's not zero because of the cases you have shut 5 down. There has been now 23, 24 in the past ten 6 years. And is it 5, 10, 15 percent? I'm saying if 7 it is 5 percent or 10 percent of those who are in 8 the gray zone or even evil, maybe .1 percent, we 9 are trying to reduce that number. And that's 10 really our purpose. That's the whole purpose of 11 regulatory agencies and your office is one of them. 12 So that is the -- I understand you want to build a 13 associate so you could illustrate your point of 14 view. But I don't think I have ever sat in any 15 place that all IRBs or all researcher are not even 16 close to that number, that they are really not 17 noble. 18 I think the overwhelming majority, maybe 19 we'll put this to rest -- the overwhelming majority 20 are nobel, wonderful, and well meaning. However, 21 still we have problems. And these problems, I 22 think are serious and we need to address them. 180 1 CHAIRPERSON MARSHALL: Thank you, Adil. I 2 couldn't agree more. And we need research. We 3 know some numerators, but we don't have a 4 denominator and I think that we're all agreed on 5 that. Well said. 6 Vera. 7 DR. SHARAV: I want to say to answer -- I 8 don't know who you are, but part of the issue, I 9 think, here is in fact broadening the use of 10 children in research. Until now this clause may 11 not have been used very often if at all. But, the 12 push to incorporate it into FDA regulation and the 13 really accelerated aggressive pace of recruitment 14 of children in the United States into clinical drug 15 trials is part of the reason that I am so very 16 concerned about this. Because the safeguard are 17 not there. We speak about them, if, maybe, must, 18 should. They're not there. They are not reliable. 19 Children -- younger and younger children 20 are being recruited; under this little waiver they 21 will be recruited without even parental consent 22 and Alan in a sense made real what I said in my 181 1 dissent which is that a broad number of children, 2 not those who have been adjudicated, not those who 3 there's even any proof of abuse would be 4 designatable by a researcher in search of children. 5 The fact is that there is great problems getting 6 children from responsible parents into clinical 7 trials. That's why we've got money on their head. 8 Parents are being bribed. 9 Now, again, which parents, from what level 10 of society are going to volunteer their children 11 for $645 for three-year-old children into clinical 12 trials. That's the reality. There's a protocol 13 out there that is recruiting three- to five-year- 14 old children and offering parents a bounty of $645 15 in addition to traveling expenses. So I am 16 concerned that this is a back door to get at 17 children and circumvent parental consent. 18 CHAIRPERSON MARSHALL: Vera, let me just 19 ask you, if we're talking about a very narrow 20 circumstance in which Alan identified, and, you 21 know, during the course of our working group 22 meetings we're talking about a situation in which 182 1 notifying parents or asking parental permission for 2 a child to enter the study may not be in the 3 child's best interest, whereas participating in the 4 study in terms of a risk benefit analysis could be 5 beneficial to the child, to other children 6 similarly situated if we build in, as we are 7 saying, these safeguards that are required that 8 don't necessarily pertain to other research that is 9 going on with children, what are your thoughts 10 about that? 11 DR. SHARAV: Is it life threatening to the 12 child? 13 CHAIRPERSON MARSHALL: Well, do you mean 14 the research or the problem? 15 DR. SHARAV: The problem. 16 CHAIRPERSON MARSHALL: The problem. I 17 think we would be talking about an array of -- 18 DR. SHARAV: You asked for my bottom line 19 in a sense? 20 CHAIRPERSON MARSHALL: Right. 21 DR. SHARAV: If it's life threatening, 22 then I will entertain it and wondering who decides 183 1 which child goes into which arm there are problems. 2 I mean, that's one thing. 3 The other thing is, in the working 4 committee we did discuss a bit, and it was kind of 5 rejected, I asked, well, if it's so very specific 6 as you have just outlined it, then it would have to 7 be -- that language would have to be in the 8 regulation, but it's not. The regulation is broad- 9 based, it's children, it does not -- regardless of 10 the recommendation in the letter, it is not 11 restricted to a specific age group or maturity or 12 anything else; right? 13 Nor -- and this is a big concern, an adult 14 -- a waiver of informed consent for an adult is 15 only for minimal risk research. Children though 16 with waiver you're talking about any level of risk. 17 There's no restriction there. You're talking risk 18 benefit analysis, what level of risk? Slightly 19 more than minimal risk? It can be any risk. 20 Nothing is restrictive in the language of 508(c). 21 CHAIRPERSON MARSHALL: Yes, but I think 22 we're disagreeing on the point of whether what 184 1 we're talking about constitutes a waiver or not. 2 And Greg has asked for the final word and 3 then I want to come to closure and we need to go to 4 lunch. 5 DR. KOSKI: The final word. Mary Faith 6 always gets the final word. Lest there be any 7 doubt whatsoever, I just want to reiterate that 8 Adil and I share completely the goal. There is no 9 controversy about that. 10 MR. BARNES: Could I make a suggestion 11 about sort of concritizing this and perhaps moving 12 on as a person who is not a member of the working 13 group? I mean, I heard a few things said today, 14 you know, in this discussion. One was -- and, 15 again, not to load up the letter with too many 16 other problems, but a better definition of 17 beneficial or some definition -- a better 18 definition or some definition of mature and a 19 clarification that that is what we are talking 20 about as opposed to either emancipated minors or 21 other categories. The idea of very careful case- 22 by-case consideration by the IRB of circumstances 185 1 in which they would allow a mature minor to consent 2 in the situation. 3 The suggestion that one of the mechanisms 4 that might be used by the IRB was the use of an 5 independent child advocate, as one not an exclusive 6 possibility, but one possibility of dealing with 7 that with a case-by-case discrimination, the idea 8 perhaps not life threatening, but what we would 9 probably be talking about here when an IRB would be 10 talking about would be medical conditions that have 11 significant mortality or morbidity, not marginal 12 gains in mortality or morbidity in most cases. And 13 finally, the idea that what we are encouraging as a 14 procedural matter for the FDA to do is either to 15 take an aggressive interpretation of its underlying 16 authorizing legislation or regulation or if 17 necessary change its regulation in this regard. 18 And what I would suggest that we do is 19 that -- I mean, if people can agree that those were 20 the major points -- I think they were the major 21 points that were made, then let Alan, you know, go 22 back, use his incredible skill and background 186 1 knowledge of this particular issue more than any of 2 us, I think, perhaps who knows about this issue to 3 include these comments in the letter. And then 4 since there is a real time pressure to get it out, 5 what I would suggest is that, you know, we have two 6 and three people who might volunteer either from 7 the working group or from the committee simply that 8 Alan could share it with and then they could give 9 him the sign-off to go ahead and do it and delegate 10 the authority of NHRPAC that way in order to speed 11 the process. 12 CHAIRPERSON MARSHALL: Thank you. That 13 was the exact sort of closure that I was looking 14 for. Committee members are you comfortable with 15 this? Alan. 16 DR. FLEISCHMAN: I am more than 17 comfortable. 18 CHAIRPERSON MARSHALL: Volunteers to 19 assist Alan to review the letter? Volunteers to 20 review the letter? 21 Okay. Thank you very much. Thank you for 22 a good morning. We will adjourn for lunch and we 187 1 are back at 1:30. Thank you all. 2 [Whereupon, at 12:35 p.m., the meeting was recessed 3 to be reconvened this same day at 1:30 p.m.] 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 188 1 A F T E R N O O N S E S S I O N 2 [Time noted: 1:35 p.m.] 3 CHAIRPERSON MARSHALL: Welcome back. 4 We have asked the staff of the Office for 5 Human Research Protections to brief us as a 6 committee on their current organization, perhaps 7 speak to plans for the future. But we thought, 8 Kate and I and Greg, that as a working group that 9 it was important for us to know as we moved along 10 with our work what was happening with a relatively 11 newly formed Office for Human Research Protections 12 and what each of its old and new offices or 13 subcompartments was all about. So we've asked Dr. 14 Koski, Greg Koski to give us an overview and 15 introduction. 16 Then we are going to hear from various 17 staff members at the Office from Jeffery Cohen who 18 is the Director of the Division of Education; 19 George Gasparis, who is the Acting Director of 20 Division of Assurances and Quality Improvement; 21 then we hear from Kristina Borror, Division of 22 Compliance. 189 1 Well, Greg, I don't believe Melody is here 2 today, but Dr. Koski, you are going to make that 3 presentation as well. And Irene Stith-Coleman is 4 with us who is director of the Office of Policy, 5 Planning, and Special Projects. So, those of you 6 from OHRP, thank you very much for giving us your 7 afternoon and to tell us about you and what you are 8 all about. 9 DR. KOSKI: Thank you, Mary Faith, and 10 welcome back everybody. 11 Now, we often talk about OHRP in these 12 meetings and, you know, I often feel kind of like 13 that thing out there on the bow spright sometimes, 14 you know, sort of the waves coming up and splashing 15 me in the face from time-to-time. But there is 16 really a huge sort of ship and a great crew that 17 are behind this sort of figurehead and we thought 18 that it would be very valuable to have an 19 opportunity for you all to meet some of them to 20 hear some of the stuff that's going on. 21 I just wanted to very, very briefly sort 22 of give you an overview of how the office is 190 1 constructed and talk very briefly about some 2 upcoming initiatives, and then introduce the 3 members of our team who are the ones that are 4 really making things happen. And so we will get 5 right onto that. 6 As you know from our previous discussions 7 here, OHRP was actually created last June. 8 Actually, it was created in April and I think it 9 became official in June and was basically 10 established within the Office of the Secretary at 11 HHS in order to provide an appropriate platform for 12 both leadership and exercise of responsibilities. 13 And the Office, as it is currently constructed, was 14 basically established to serve not only the need to 15 sort of reach up and out, but also, you know, 16 within organizations it has a very broad kind of 17 role with some key functional activities, 18 operational activities; and I think the structure 19 of the office reflects that. 20 We have the Office of the Director in 21 which I spend, you know, my professional life. 22 It's basically the office where we provide the 191 1 central coordination for all that goes on. And our 2 administrative officer, Gary Rice, who is, I don't 3 think, here today. And Tony Goodwin who runs the 4 Executive Secretariat function within our office. 5 They play critically important roles. Tony, I 6 think, is outside at the table, again, sort of 7 keeping things going. 8 But we also have sort of branching off of 9 the Office of the Director two component offices. 10 One of those is the Office for Planning Policy and 11 Special Projects that Dr. Irene Stith-Coleman heads 12 up for us and she'll be talking to you. That's an 13 office that has to deal with just a vast array of 14 things that come up that don't fit into the 15 otherwise sort of ongoing operational activities of 16 the office. 17 We also, last year, created the Office for 18 International Activities to serve a focal point, a 19 coordinating center, kind of the one-stop shopping 20 process to tap into the functional or operational 21 details of the office in a way to address the 22 growing need for coordination of, again, a host of 192 1 activities in international conduct of human 2 research. 3 Dr. Melody Lin, our Deputy Director has 4 also agreed to serve in the capacity as the 5 Director of that Office for International 6 Activities and I'll talk to you about that in a 7 minute. 8 But the real meat of the office's 9 activities are carried on by the three operating 10 divisions there. One of those, the Education 11 Division, headed up by Jeff Cohen, I think you all 12 know Jeff. The Compliance Oversight Division which 13 is headed up by Mike Carom, and then the new 14 division for assurances and quality improvement 15 that currently George Gasparis serves as the Acting 16 Director for that. And I think one of the key 17 steps in moving our office from what had been a 18 compliance-based sort of focus to one that is truly 19 looking forward toward outreach interaction, 20 prevention of harms, which is what we all really 21 want to do, focusing on performance of the whole 22 human research protection system in a 193 1 forwardlooking manner rather than looking back to 2 see where there have been failures. 3 The extent to which we can prevent 4 failures to where we can really focus on our true 5 goal of protecting human subjects and actually 6 promoting the responsible conduct of research is 7 something that will serve all of our interests. 8 Now, last September we laid out our sort 9 of plan for remodeling in the testimony that I gave 10 before the House Committee on Oversight of Veterans 11 Affairs. We described a host of activities there 12 and I'm very happy to say that we have moved ahead 13 with each and every one of them and basically 14 accomplished, or at least have initiated pretty 15 much all of them. These studies are on time and 16 under budget which is a good place to be in 17 government and we'll talk more about some of those 18 things. 19 We have, of course, had to deal with, you 20 know, certain things that pop up in government 21 administratively that have made it challenging at 22 times, but I'm very happy to report to everyone 194 1 that in fact all of the positions that had been 2 authorized for our office, we had been given 3 approval to go ahead and fill all of those 4 positions and we have outstanding people who will 5 be joining our office soon which will bring our 6 compliment of full-time personnel from the current 7 level of 24 which is actually lower than what we 8 started with, up to the 47 that it's supposed to 9 be. So, I think that's a very, very positive sign 10 and we're very excited about that. 11 The things that I'm sort of, in terms of 12 new initiatives that are out there, that are coming 13 that people should be aware of, and, again, you may 14 get more detail on this as you hear the individual 15 presentations, one of them is the implementation of 16 our new quality improvement program that we are 17 extremely excited about. We will actually -- 18 currently it's in pilot testing. We hope that as 19 early as right after Labor Day we will begin to 20 scale it up to full scale. 21 When it's in place it will be a voluntary 22 program that George is going to describe, but we 195 1 will actually be reaching out and interacting with 2 some 60 sites every month which is a new sort of 3 trend. It's a program that is voluntary in nature, 4 but, again, focused on achieving real performance 5 in the system. 6 So you will hear more about that from 7 George. We also have upcoming what we have 8 referred to as our SUEE task force. The "SUEE" is 9 an acronym that stands for Simplification 10 Uniformity Efficiency and Effectiveness, which 11 clearly, I think you would all agree is something 12 that within government would serve everyone's needs 13 well. 14 We would like to find ways to make the 15 whole process simpler, to find those things that 16 are actually working to protect the interests of 17 human subjects, emphasize those, find the ones that 18 we're asking people to go through that are really 19 not serving that need in the most effective way and 20 get rid of those. We want to try to clearly 21 revolutionize some of this and we are very happy 22 that Susan Zulo who is seated back here and who 196 1 operates out of Irene Stith-Coleman's offices 2 taking on the challenge of doing this under the 3 auspices of the Human Subjects Research 4 Subcommittee where all of the federal agencies are 5 going to be working together to achieve some of 6 these goals. 7 Another project that that group is working 8 on is a federal-wide handbook for human research 9 that would sort of pull all of the common ground of 10 human research subject protection together and to 11 what would be a valuable resource to everyone 12 engaged in the process. And, actually, Susan Rose 13 from the Department of Energy and Alyse Summers 14 from our office are working on that. Jeff may 15 mention it more. 16 Finally, I think one of the issues that 17 remains to be sort of untackled as yet is the whole 18 issue of what happens after the IRB says okay. 19 We've reviewed, approved a project, people are 20 going to be enrolled, but there is still not a 21 consistent approach to how we deal with the actual 22 people engaged in the research and the occurrence 197 1 of adverse events, the appropriate roles for 2 medical monitors and data monitoring committee, 3 safety monitoring committees, patient advocates and 4 so on. Continuing review, all of this activity 5 fits together in what has been pretty much a gray 6 zone and sort of a free style activity where done a 7 lot of different ways, a lot of different places 8 under a lot of different sort of authorities. 9 We want to pull together a governmentwide 10 task force to really focus on how we could be doing 11 that right. And we hope to do that soon because 12 it's certainly something that we need to be doing 13 well. So those are, I think, three things that are 14 coming while the rest of our activities are 15 ongoing. 16 Since what the other folks here have to 17 say is far more important than what I have to say, 18 I'm going to be quiet and turn it over overtime 19 them. I'm not sure of the order, but I believe to 20 start off -- Jeff. 21 Jeff Cohen is going to talk to us a bit 22 about the activities of our Division of Education. 198 1 Jeff. 2 DR. COHEN: First of all I want to thank 3 the committee for the opportunity to share with you 4 what we're doing in the Education Division at OHRP. 5 And our mission -- our overall mission is as the 6 name of our division says, is education. But more 7 in a broader sense of the term of education and 8 more appropriately it would be outreach, 9 communication, and really our aim goes back to what 10 Greg had said before about prevention. And we 11 believe very sincerely that the best prevention 12 method in this field is education. That most 13 people, most researchers, most institutions want to 14 do the right thing, they just don't know what the 15 right thing is, or how to do it. And so it's our 16 aim to make sure that at least is not the case. 17 And everyone, as much as we possibly can knows what 18 the right thing to do is, and how to do it. And so 19 we're working very hard in that effort. 20 We focus basically in three main areas. 21 Presentations and training programs, workshops and 22 town meetings, and then finally educational 199 1 materials. And let me go through those three and 2 tell you what we are doing and what we plan to do 3 in the future. Hold on one second. 4 [Pause.] 5 DR. COHEN: Okay. Just double checking on 6 what the current thinking is. 7 [Laughter.] 8 DR. COHEN: That's about as current as it 9 gets. 10 [Laughter.] 11 PARTICIPANT: At least he understands how 12 it works. 13 [Laughter.] 14 DR. COHEN: Let me start with the 15 presentations and training programs. We do a great 16 deal of outreach. We try to make ourselves 17 available for giving presentations. We give 18 presentations at professional society meetings. We 19 give presentations at universities, medical 20 centers, government agencies, IRBs, groups of 21 researchers, we gather people on the street corner, 22 we grab them walking down the street. Any 200 1 opportunity to get the word out we will take and 2 we've got a standing offer and we try to fulfill 3 all of the requests that we possibly can fulfill. 4 Just this year alone we've given well 5 upwards of 60 presentations in different 6 organizations and settings. We've also done some 7 more focused training programs at institutions for 8 IRBs, for institutions that have come to us and 9 asked us to do training for their investigators. 10 We tend to try and avoid, because it's 11 impracticable -- using a famous word -- 12 "impracticable" -- I don't even know if there is 13 really such a word. 14 There is no way we could fulfill all of 15 the requests. If we were to get -- the demand is 16 infinite. We could have 100 people on the road all 17 of the time, seven days a week, and not fulfill the 18 demand. And so what our focus is on the 19 presentations and training programs, is to try and 20 get groups of people together. So we try to avoid 21 going to a single institution and doing a training 22 program for that institution just because it's 201 1 impracticable. And so what we encourage people to 2 do and wherever is to bring together groups of 3 institutions, IRBs from various institutions, 4 various research centers, faculty together and do 5 them as groups. And that's our focus in that 6 respect. 7 We also have a series, a sort of a formal 8 series of workshops and town meetings. Let me 9 explain the difference between a workshop and a 10 town meeting as we use the terms. A workshop is a 11 general program. It's sort of the traditional 12 program, presentations, breakout sessions and 13 discussion groups, for large groups. We hold these 14 around the country, and they are open to enrollment 15 to anyone. 16 The town meetings are more like day-long 17 question and answer sessions. Because the feedback 18 that we get from our workshops is that there is not 19 enough time for questions and answers. And so we 20 came up with the concept of a town meeting where we 21 provide -- there is very little in terms of 22 presentations or didactic material and it's almost 202 1 totally question and answer. Sometimes focused, 2 sometimes broad, but plenty of opportunity for 3 questions and answers. 4 This year we did -- we have already done 5 five workshops and we have one other one planned in 6 September. We did workshops in Washington, D.C., 7 Honolulu, Newark, Charleston, and Los Angeles and 8 our upcoming workshop in September, a little plug, 9 September 20th and 21st in Minneapolis at the 10 University of Minnesota. 11 One of the main features, and I think one 12 of the most exciting features of these workshops is 13 that it's not just an OHRP workshop. These are 14 joint workshops which we are doing with the 15 Veterans Affairs, ORCA, the Office of Research 16 Compliance and Assurance form Veterans Affairs, the 17 Food and Drug and Administration, the National 18 Institutes of Health. 19 At our last workshop in Los Angeles, last 20 month, not only did we have those three agencies, 21 but we had representation for the National Science 22 Foundation, Department of Education and Department 203 1 of Energy. So it really is an opportunity, and one 2 of the great feedbacks that we get on these is it's 3 a great way to see the feds. They actually see us 4 that we're real people, we don't bite, you know, 5 and give them an opportunity to pigeonhole us and 6 talk to us. And so we're very proud of the fact 7 that these are joint workshops from many federal 8 agencies. 9 And we also encourage the other federal 10 agencies who are represented in the room to join in 11 with us in future workshops. And we are in the 12 process of planning next year a series of workshops 13 and we are again planning about five or six 14 workshops for the upcoming year. 15 Our town meetings, we did three town 16 meetings this year, one in Dallas, one in Boston, 17 and one in St. Louis. Our Boston workshop was an 18 experiment, we got informed consent, I guess, 19 verbally, apparently. We did that. That was our 20 first video town meeting. And we did that as a 21 two-way interactive video town meeting, except the 22 fact that Greg was at the site, we were here. All 204 1 of the representatives from the federal agencies 2 were here in Washington. The audience was in 3 Boston, and we got very good feedback. It went 4 very well. Susan Kornetsky was in the audience and 5 I think it went very well. And it went so well 6 that we are planning future video town meetings. 7 The town meeting format lends itself to the video 8 -- interactive video method. 9 Finally, with the education materials and 10 this is an area where we haven't devoted as much 11 attention as we would have liked to just because 12 we've been focusing on the other two areas, 13 primarily. The educational materials that we offer 14 right now are our IRB guidebook and our videotape 15 series. Unfortunately, our videotape series dates 16 back to 1986. The guidebook dates back to 1993. 17 So we have planned this year -- fully staffed and 18 resourced, we will be updating both of those. 19 And the guidebook, as Greg mentioned, our 20 efforts with updating the guidebook is federalwide. 21 We are going to be working with other federal 22 agencies who have already begun and Susan Rose has 205 1 already begun the effort. So it will be a 2 federalwide guidebook and not just an OHRP 3 guidebook. 4 Finally, we have in terms of new 5 initiatives, we began this year what we call our 6 OHRP mailbox. And we see this as part of our 7 education effort. And this is a question and 8 answer mailbox. We have an e-mail address, 9 ohrp@osophs.dhhs.gov. You know, I say that a lot. 10 And we see that as our question and answer mailbox. 11 Anyone can send any question they want about human 12 subjects research, anything about ethics, 13 regulations, what OHRP is doing, anything at all, 14 and we assign staff to review that mailbox on a 15 daily basis and get back to people as quickly as 16 possible with an answer. And so we are going to be 17 beefing that up and trying to provide as much 18 feedback to people as we can and answer their 19 questions. 20 Finally, one more new initiative which we 21 began this year and is going to be continuing which 22 we are really only a part of, but we helped get 206 1 started, is what we called in the initial phases 2 our education summit. We brought together along 3 with the Office of Research Integrity people 4 involved from the private sector, from 5 institutions, from industry, from federal agencies, 6 everyone involved in education and responsible 7 conduct of research in the broadest sense of the 8 term, not just human subjects research, but all 9 responsibility conductive research. And to discuss 10 how we could best coordinate, facilitate, make it 11 easier for institutions to do the kind of training 12 that is necessary for their faculty, for their 13 researchers. 14 Our first meeting was back in February. 15 It was very exciting and one of the main 16 conclusions of that meeting was that there needed 17 to be a body, an independent body, not a government 18 body, but an independent body to somehow perform 19 this function. And so where the group is meeting 20 again this August to actually kick off and create a 21 body which right now we would be calling the 22 Education Council. And it's goal will be to 207 1 coordinate education efforts to be a clearinghouse 2 of educational materials, educational programs, and 3 to really try -- the goal is to make it as easy as 4 possible for institutions to do the kind of 5 training and education of their researchers that 6 they need to do. And so we are very excited about 7 that. Especially since we are not doing it. It's 8 a public/private partnership which is really the 9 best way to go. So all of these things will come 10 out of the research community with our involvement. 11 So we are very excited about our education 12 programs. We are going to be doing even more. 13 Like I tend to say to people, you are going to be 14 sick of us by the time we are done, you are going 15 to hear so much from us. 16 So thank you for this opportunity. If 17 anybody has any questions. 18 DR. MORENO: Thanks Jeff. I have two 19 questions. Actually, first I want to acknowledge 20 that you've agreed to come to Charlottesville for a 21 workshop and remind you of that. 22 DR. COHEN: Yes. 208 1 DR. MORENO: And thank you for that. 2 Granted that we don't have 100 people to do these 3 things. How many FTEs do you have to do education? 4 And the second question is, the mailbox idea sounds 5 like a great idea. It also scares the hell out of 6 me from your point of view because I could imagine 7 that you could be inundated with questions that are 8 quite technical in nature and how are you -- I'm 9 sure you've thought about this, but how are you 10 going to assure that the responses that you get 11 have some consistency, that you give have some 12 consistency. 13 DR. COHEN: Right. Let me start with the 14 mailbox question first. And that is that the way 15 we've been working it and we've had a lot, but not 16 inundated at this point. But the way we've been 17 working it is we have someone assigned to review 18 the mailbox. That person, from our staff, is an 19 experienced person, so the simple questions she can 20 answer herself. And then the questions that she 21 doesn't feel that she can answer, we tend to 22 circulate amongst the staff at OHRP to get a 209 1 consensus answer and whoever is best suited to 2 provide that information. 3 I'm sure there will be a point, a volume 4 point where we are going to have to try to come up 5 with a better procedure, but we are committed, I 6 think this is a very important effort. Because one 7 of the things that we get -- comments we get all of 8 the time is, we don't know what to do, we don't 9 know what the answer is and we can't wait for a 10 conference or we can't wait, you know, we need some 11 feedback fairly quickly. And so I think it's a 12 very important effort and we are committed to 13 trying to make it work. And we do always tell 14 everyone, we're always willing to entertain 15 hypothetical questions. We have -- I know of this 16 institution who is doing this -- 17 [Laughter.] 18 DR. COHEN: -- is that okay, you know. 19 [Laughter.] 20 DR. COHEN: As far as the FTEs are 21 concerned, I believe we currently have -- there are 22 three of us in the education division. At this 210 1 point in time we lost some ground. We have plans 2 for adding, I believe, four or five people to that. 3 Those are still under development as we've now been 4 able to move into a new effort. And I should 5 mention also, very importantly that it's not 6 limited to the education division that we call on 7 the entire staff of OHRP in our education effort 8 and whenever people are available and are 9 appropriate, we call them in and bring them into 10 the education effort. So the whole office is 11 committed to the education effort. 12 DR. DORFF: I know you're not looking for 13 more work, but one of the things that you may want 14 to think about is creating a unit for college and 15 graduate students to prepare them -- who are going 16 to be going into research of one sort of another, 17 just to give them a heads up while they're in 18 training about the importance of this stuff. 19 DR. COHEN: Yes, that's a very good idea. 20 We are looking for more work. We are looking for 21 new, particularly in terms of materials, brochures, 22 guidebooks, we do want to do more of that. And so 211 1 we will be actually looking for new ideas. 2 AUDIENCE PARTICIPANT: [Off mic.] 3 DR. COHEN: Many medical schools do. And 4 I think it's a growing number that do. And, of 5 course, the NIH training grant requires such a 6 course. And so any institution that has an NIH 7 training grant has to have a course like that. So 8 there is a growing number of courses. Bob, maybe 9 you would know a little more about that. 10 DR. R. LEVINE: I wanted to bring up a 11 different topic. Given your limitations in 12 resources, there is an organization that has been 13 out there trying to educate people on IRBs and IF 14 -- for getting on to 30 years now, the Primer 15 Organization. There are three members of the board 16 here at this table and they can assure you that I'm 17 not speaking for them or the organization. But I 18 would like to know in what way you think your 19 educational program compliments or supplements what 20 Primer has been doing all along? 21 DR. COHEN: Oh, absolutely. I don't think 22 anyone can doubt my allegiance to Primer. But, 212 1 yes, we see that as a supplement and we also work 2 very closely with Primer at their conferences and 3 provide speakers and resources. We see it as 4 complimentary. 5 DR. R. LEVINE: I didn't ask my question 6 well. Is there something in the efforts of Primer 7 that left a gap that you felt impelled to fill? 8 DR. COHEN: I think the main -- and, 9 again, it's why we tended to focus on the group 10 presentations because that was an area that -- 11 Primer was particularly with its IRB 101 program, 12 it does an excellent job going to individual 13 institutions and helping them educate their 14 faculty. And that's why we moved away from that 15 focus. And there was a need to do it in a larger 16 group setting. And the Primer meetings are 17 wonderful, but only so many people can attend 18 Primer meetings. 19 DR. R. LEVINE: Let me say that 101 is one 20 of the things that Primer has been doing in the 21 last few years. But their large scale meetings 22 which were held as national meetings, I don't know 213 1 how many people applied to go to them, but at our 2 last meeting we started turning people away when 3 the registration hit 1400. 4 DR. KOSKI: If I could just -- you asked 5 about gaps. I think that we do have, in fact, 6 three serious gaps in education that we need to 7 fill. One of those is the investigative community. 8 Okay. The people that tend to come to the primer 9 community are the people that are already committed 10 to doing this particular thing. Not that 11 investigators are not, but it's not something that 12 fits into the regular daily life many time of the 13 investigators. And that's, in my mind, a problem. 14 Increasingly though, we are seeing 15 investigators taking advantage of opportunities for 16 education, and, indeed, the investigator 17 certification program that the Association of 18 Clinical Research Professionals has now launched is 19 taking off, you know, great guns so that people are 20 going there. But I think everyone recognizes the 21 need to educate all the way up and down the chain 22 here, the chain of command, and that points to 214 1 another gap. 2 I think that oftentimes the people at the 3 very top of our institutions and companies and all 4 are people who could benefit from having a greater 5 interaction with this particular segment of the 6 human research community. And so we are, again, 7 looking for ways to do that. 8 But, finally, I think the most serious gap 9 in the whole thing is the lack of understanding 10 that the public has about the nature of the 11 research process. The expectation that research is 12 risk free is a problem. And the lack of awareness 13 of the entire IRB process is a problem. 14 The lack, of understanding of what the 15 informed consent process is all about is a problem. 16 And I think as we go forward we have to focus on 17 not just educating IRB members and chairs and 18 investigators and all, but really get the message 19 out there to the American public about what 20 research is really all about. Because that's the 21 single best way to improve the informed consent 22 process, have people who are coming in who might be 215 1 interested in participating in the research to 2 better understand the process and what's involved 3 early on. 4 MS. BORWHAT: Related to what you just 5 said, public outreach, do you have any plans to do 6 the workshop or the video on the web as well? And 7 are any of the materials presented at the workshops 8 or the educational presentations available on the 9 web? 10 DR. COHEN: Not currently, but that is in 11 our plans. We are looking at how we can best both 12 the actual presentations themselves and the slides. 13 We are working with -- our last workshop was with 14 the University of Southern California and they 15 video taped the workshop and we are working with 16 them to explore digitizing that workshop and 17 putting it on the web. So we are looking at ways 18 to do that to get that accomplished. 19 And let me mention, because Margaret, I 20 already had a conversation about this earlier, the 21 role of community members on IRBs, and we are 22 looking at focusing some training on those 216 1 individuals because they have a special need and a 2 special role to play. And that's one of the areas 3 that we've already talked about. 4 DR. KORNETSKY: As a member of the IRB 5 community that uses the educational services of 6 your office, I think it's important for this board 7 to understand that there's really been great 8 improvement over the past year and that they really 9 are very receptive and I think whatever we can do 10 to get the word out to people not to be afraid to 11 call and use the educational services and have 12 their questions answered is worthwhile. Thank you. 13 DR. COHEN: One of the things that I say 14 whenever I give a talk is no one ever has and I 15 don't think anyone ever will be investigated based 16 on a question. And so people don't have to worry 17 about asking questions. 18 CHAIRPERSON MARSHALL: Jeff, maybe I'll 19 just make one final remark and that is to commend 20 you on your wonderful work in the education area. 21 And it truly is the most important thing, I think, 22 in terms of prevention. One other thought aside 217 1 from the tremendously important top down and bottom 2 up idea of educating institutional CEOs and deans, 3 and perhaps chairs of promotion committees and so 4 forth, as well as research participants themselves 5 and the public, might be a focus on science 6 journalists and science writers. Because I think 7 they play -- as we know, if we look back at the 8 history of research ethics and sort of crisis and 9 response, that many of the stories that we first 10 heard about are the cases such as Tuskegee and 11 others, we heard about through science journalists. 12 And I think responsibility reporting is something 13 that will go a great way towards educating the 14 public as well and perhaps focusing on science 15 writers would be a good thing. 16 Thank you very much. 17 MR. BARNES: Could I ask one final 18 question, please, if you don't mind. Just quickly. 19 You know, do you have any relationship to -- have 20 you ever done any public education with HCFA -- 21 with CMS? And I'm particularly wondering because 22 one of the issues that IRBs are grappling with 218 1 right now is -- because it's required by the common 2 rule, instead of determining the informed consent 3 process, what do patients have to pay for and what 4 don't they have to pay for? Which in turn is 5 governed by the guidance that was put out by HCFA 6 which is quite opaque in its interpretations. 7 And I say that, you know, HCFA has its own 8 web site, and I'm glad that you can answer all your 9 questions, because clinical trials at HCFA.gov 10 doesn't answer all of the questions posed to it, I 11 can assure you. And, I mean, this is a real 12 practical question that IRBs are really grappling 13 with it. If you have reached out to CMS, I would 14 really encourage you to try to do some joint 15 presentations with the staff of CMS. 16 DR. COHEN: I think that's an excellent 17 idea. We have interacted with them and in part to 18 help bring them up to speed in terms of their 19 developing their policies. But I think that's an 20 excellent idea to do some joint programs with them 21 to focus on that issue would be -- you know, we 22 would be happy to do that. 219 1 DR. R. LEVINE: If I could comment on 2 that. I think that HCFA has been concentrating 3 recently on the sort of clinical trial, the 4 prototype for which was the National Emphysema 5 Treatment Trial where HCFA took the position that 6 it would not pay for services that were going to be 7 evaluated in the National Emphysema Treatment 8 Trial, in particular, it wouldn't pay for the lung 9 reduction surgery unless the patients agreed to be 10 randomized in the NETT trial. And since that model 11 was introduced there have been other things having 12 to do with cardiovascular devices and so on. But I 13 don't think HCFA has addressed generally what would 14 be called for by way of payment for various types 15 of therapies that are being evaluated. 16 MR. BARNES: It actually has, Bob, because 17 it put out a guidance document in September of last 18 year which it is now trying to interpret it own 19 guidance document. But there is a general guidance 20 document that was issued which has many gaps and 21 that sort of thing. 22 CHAIRPERSON MARSHALL: Is it Mike? 220 1 MR. SUSKO: [Off mic.] 2 CHAIRPERSON MARSHALL: Could you please 3 use the mike. I'm sorry, we need to tape our 4 proceedings. 5 MR. SUSKO: Yes, my name is Michael Susko 6 from CIRCARE. Just one group that I don't think 7 should be omitted in the whole general rubric of 8 education would be the people who are likely to be 9 enrolled in these projects. And like at the 10 various drop-in centers and soup kitchens, they're 11 getting phone calls, the institutions are calling 12 and asking about their research subjects. So maybe 13 that would be a place you could leave literature 14 around so that people might be able to aware of 15 their rights, the people who can read that are in 16 that group. But just don't forget that group. 17 DR. COHEN: I think as Greg mentioned, the 18 whole area of public education and education of 19 potential subjects, wherever they are is high on 20 our list. We haven't had the resources to get to 21 that yet. But we are very committed. That's a 22 very, very, very important issue. 221 1 Like they say with used cars, the best 2 protection is an informed consumer. And so we 3 really are -- that's on our list and we really do 4 want to approach that at all levels. 5 CHAIRPERSON MARSHALL: Thank you, Jeff, 6 very much. 7 Next we have George Gasparis who is the 8 Acting Director of the Division of Assurances and 9 Quality Improvement. 10 MR. GASPARIS: Good afternoon. It's a 11 great pleasure to be with you this afternoon to 12 share the workings of our division and our new 13 initiatives. And I also would like to express a 14 sincere thank you to NHRPAC for inviting me here. 15 Our division used to be called the 16 Division of Policy and Assurances, and under the 17 restructuring has been moved to the new title, 18 Division of Assurances and Quality Improvement. 19 I would like to take a moment to recognize 20 our rather small division, or I would call it a 21 small division considering the enormous workload 22 that we have facing us. Roslyn Edson, Dr. Kamal 222 1 Mital, Frieda Yoder, Janice Walden who joined us 2 recently, and we have been fortunate to also have 3 help from outside the division with a Dr. Sharkey 4 and Dr. Nasbatin who is in the audience today, 5 helping in with the division, and we have one 6 support staff Denise Dejarne. 7 Real quickly, I think there's only one 8 person of the division here business of other 9 obligations. Dr. Batins, if you could stand. And 10 was Frieda able to make it this afternoon? I guess 11 not. 12 Kamal is attending a conference and Cliff 13 is out of town and the others are holding up the 14 fort while I'm here this afternoon. 15 Actually, I do prefer to probably stand up 16 -- since I'm using PowerPoint -- if you can hear me 17 clearly; otherwise, I'll sit back down closer to 18 the microphone. 19 Real quickly, I want to go over our old 20 system of assurances of compliance so you can 21 understand why we felt the need to revamp a system 22 and move to a new system. 223 1 We have three general types of assurances 2 in the past: a multiple project assurance, 3 cooperative project assurance, a single project 4 assurance. And the later two we adopted through 5 international sites. And that adaptation was that 6 they could reference other standards -- procedural 7 standards, for example, C-owns and other ethical 8 principles, the Declaration of Helsinki rather than 9 the Belmont Report and our regulations. 10 Real quickly, just to share with you the 11 fundamental aspect with each of these assurances, 12 and assurance is simply a written commitment from 13 an institution engaged in human subject research 14 supported by the Department or the federal 15 government under the common rule that they provide 16 to us a commitment that they understand the 17 regulations and will comply with them. 18 Starting with the lowest level of 19 assurances, single project assurance, we internally 20 reviewed the individual brain application and 21 proposed informed consent form because we felt that 22 these were smaller institutions that did not have 224 1 an experienced IRB to review that research. Under 2 the cooperative project assurance, what we reviewed 3 was the infrastructure in place with the design of 4 the protocol and the informed consent, and we felt 5 competent that these multi-center trial were 6 managed properly and with sufficient expertise that 7 we could approve institutions over a CPA for a 8 five-year period for any research under a 9 cooperative protocol which falls under this 10 program. And these are the famous oncology trials, 11 AIDS clinical trials group which put out pretty 12 polished products. 13 And under the highest level of assurance, 14 also for a five-year period, we approved the major 15 institutions and academic medical centers under a 16 multiple project assurance because they had proven 17 to us in the past that the IRB had sufficient 18 expertise that we could rely upon that institution 19 to conduct their own review, and we didn't have to 20 review that project internally. 21 Well, what we found happening in our 22 office was a significant increase in volume 225 1 especially since 1995, and just from 1999 alone to 2 2000, we had a 48 percent increase in workload 3 under the single project assurances. This was a 4 tremendous workload that made it almost impossible 5 for us to review each individual project. And 6 toward the latter part of 2000, we had to turn away 7 the individual reviews of those protocols and put a 8 disclaimer on our approval letters that we did not 9 review the informed consent for that document. 10 So, we felt the need to move to a new 11 assurance system in which we would treat every 12 pretty much equally even though every institution 13 wouldn't be at the same starting place, and include 14 in this assurance more education and then approach 15 each institution down the road and work more 16 closely with the IRBs to strengthen the overall IRB 17 system. 18 So, under Greg's leadership towards the 19 end of last year, we did release the federal-wide 20 assurance, the new assurance mechanism under a 21 pilot program thereby eliminating all the 22 permutations of the old system making it a much 226 1 simpler system which there is one assurance 2 document per institution and we still manage to 3 keep the flexibility for international 4 institutions. All institutions are eligible for a 5 federal-wide assurance which has great significance 6 which it means that an institution no longer has to 7 wait for a grant to be awarded to apply for an 8 assurance, i.e., a single project assurance. 9 Therefore, we are removing the hold up with a 10 regulatory burden in which research is being 11 delayed for our review. 12 Eventually the federal-wide assurance will 13 be entirely web-based, meaning that an institution 14 can submit to us electronically and receive an 15 electronic approval, but by no means are we 16 limiting or eliminating any institution that 17 doesn't have access to the internet they could 18 still submit the federal-wide assurance under a 19 paper submission and this is of most concern 20 perhaps to some international organizations that do 21 not have the same technological capabilities that 22 we have. 227 1 For the federal-wide assurance we broke it 2 down into a two-step process where the IRB, whether 3 it's the own institutions IRB or another outside 4 IRB would have to register in our database and we 5 worked closely with FDA to develop our IRB 6 registration which was jointly released with the 7 federal-wide assurance. Under the IRB registration 8 system, any IRB can submit to us for registration. 9 There is no requirement that they review federally 10 funded research. 11 The IRB submission process is very simple. 12 It's downloading a three-page form which could be 13 completed in a matter of a half hour or less. And 14 one advantage for an IRB to register with us is 15 that we can notify them of any upcoming new 16 guidance, new policies being released by our 17 office, or any new information which we think would 18 be helpful to them. 19 Anyone can track any approval of an 20 assurance or any IRB that's been registered on our 21 web site. 22 I mentioned how we handle the assurances 228 1 because with the single project assurances, 2 remember, we are no longer going to review these 3 individual protocols. So, we felt that we had to 4 strengthen the federal-wide assurance mechanism by 5 emphasizing the need for education. 6 One aspect of the federal-wide assurance 7 that we did not handle properly or as well as we 8 should have when we released it was to clarify the 9 difference between our assurance training modules 10 which we produced three assurance training modules 11 for the signatory official, human protections 12 administrator, and IRB chair to complete for 13 submission of a federal-wide assurance versus 14 educational training. 15 First of all, the assurance treatment 16 modules we do not consider to be educational 17 training, but rather training towards the essential 18 requirements of the responsibilities under an 19 assurance. 20 Education training, on the other hand, we 21 feel is essential for the IRB, its chair, members 22 and staff, and for investigators and we do 229 1 articulate the need for educational training by the 2 institution under the federal-wide assurance. 3 Such training should cover ethical 4 principals, the regs, state law and institutional 5 policy. 6 Well, what is our experience so far under 7 federal-wide assurance? Well, to date, "to date" 8 being Friday afternoon with any approval entered in 9 our database, we've approved 789 federal-wide 10 assurances and we've approved 804 single project 11 assurances. For seven months, it may not seem like 12 there was much difference here with a pretty much 13 50/50 split. 14 I don't want to bore you with numbers, but 15 I took a look at just the past three months and 16 there's an almost seven-fold approval of FWAs 17 versus a single project assurance. What this 18 suggests to us is that our office, our division is 19 going to gain tremendous efficiency in that we are 20 going to have to spend less time on review and 21 approval of assurances and we could turn to our new 22 initiative which I'll explain in a moment. 230 1 Recall that federal-wide assurance is 2 approved for a three-year period. A single project 3 assurance is approved for only that individual 4 grant. So once an institution has a federal wide 5 assurance we will gain tremendous efficiencies by 6 the diminishing need of review of assurances in the 7 future. 8 We have received many comments from other 9 federal agencies, the public, IRBs, on our federal- 10 wide assurance, on confusion about how to apply it 11 for certain institutions. Again, by going to a 12 one-model-fits-all, we tried to fit all the 13 necessary responsibilities of an assurance under 14 one document. That's difficult to do when you 15 apply it to a large institution conducting research 16 versus a nursing home with just a school that is 17 engaged in one or two projects. 18 So, we gained from all the comments 19 submitted, we drafted new versions of the federal- 20 wide assurance, it's terms and the IRB registration 21 form which we think will serve just or answer to 22 the criticisms and the comments that we have 231 1 received so far and we do feel that the final 2 products will be very useful in application to all 3 types of institutions. 4 Once we finalized these versions, we will 5 submit in the very near future to OMB for clearance 6 of these final documents and we will release them 7 on our web. 8 Under Dr. Koski's leadership, we have 9 implemented our new initiative which we feel is 10 necessary, especially for those smaller 11 institutions which under the single project 12 assurance we didn't have confidence that the IRB 13 could review as well as an MPA institution. But we 14 feel that all IRBs, because of the amount of burden 15 facing them, do need some assistance and we need to 16 ensure that they are doing the best job possible. 17 Therefore, under our new program we have 18 objectives to improve the performance, quality, and 19 effectiveness of IRBs, and secondarily to help them 20 ensure compliance with the regulations. 21 As Dr. Koski mentioned, it's a voluntary 22 program for institutions and we will approach this 232 1 new program under a three-pronged approach with 2 site visits, videoconferencing, and self evaluation 3 through a self-assessment tool. 4 We developed our QA self assessment tool 5 and released it just this past month to nine 6 institutions for review and comment. And as Dr. 7 Koski mentioned, we are now beginning our pilot 8 testing of the QA tool. 9 And during the questions and answers if we 10 have time, I'll leave my e-mail for any of you who 11 wish to forward any comments. 12 CHAIRPERSON MARSHALL: Adil. 13 DR. SHAMOO: Thank you. The Office of 14 Research Integrity, ORI, does not have the system 15 of assurance which is really a contractual 16 agreement between the institution and OHRP. But 17 what they do have -- and they have evolved into 18 this -- a model institutional policy regarding 19 scientific misconduct. They have published that in 20 the web, they give copies of it, they describe how 21 the inquiry stage, the investigation stage, the 22 membership, et cetera, et cetera. 233 1 Institutions are developing now 2 institutional policies parallel to scientific 3 conduct issue, how to deal with it, how to deal 4 with human research protections. 5 Now, those institutional policies varies 6 literally from A to Z. And I was wondering whether 7 one way to mainstream those fallacies is for OHRP 8 to develop a model institutional policy dealing 9 with Human Research Protections as well as, and I 10 know this will give you more work, as well as ORI 11 does it, the institution before final approval by 12 their board of trustees, or the president of their 13 institution of these policies they are giving a 14 copy to your office, for example, equivalent to 15 ORI, they review it, they send back comments, you 16 missed your -- you have all non-tenured professors, 17 or you don't have enough tenured professors, or you 18 didn't wait 30 days or 60 days, et cetera, and they 19 send it back, the institution go over it, of course 20 the institution all the time make their policy 21 slightly tougher than the federal requirements, so 22 they will be safe. And I'm saying is, could you 234 1 move in that direction and lessen the confusion 2 among institutions in developing their own 3 institutional policies regarding human research 4 protections. 5 MR. GASPARIS: I'll let Greg chime in 6 after I make some comments, because I'm sure he has 7 some thoughts on this as well. We've toyed with 8 the thought of developing standard operating 9 procedures. Your latter comments addresses our 10 difficulty with releasing such a document because 11 from our perspective our sample policies would be 12 applicable to the regulations which we govern. But 13 when an institution drafts and writes operating 14 procedures they must also consider the FDA regs, 15 they must consider state law, experiences within 16 that institution. So, therefore, there could be 17 quite a variance in the actual SOPs that each 18 institution has. 19 Under our QA program we will look at the 20 operating procedures of each institution and we do 21 have already guidance which an institution can use 22 to draft their own written policies if they 235 1 haven't. Hopefully most institutions already have 2 operating procedures for their IRBs in human 3 subject protection system because they're required 4 by the regulations. But the guidance that we 5 already have on our web site available now to 6 institutions is from the compliance division issues 7 of revolving concern. I don't think I've mentioned 8 the title, as you will see it on the web site, but 9 if you look under "compliance division" you'll 10 easily find this document. And it goes point-by- 11 point with many of the procedural concerns that an 12 institution should address in their operating 13 procedures. 14 Our self-assessment tool will also be a 15 document which an institution can use to verify 16 that their operating procedures are comprehensive 17 with respect to at least our regulations. 18 DR. KOSKI: If I could just quickly add in 19 there. Obviously we need to have a level playing 20 field across the board for all entities engaged in 21 human research, we can't have the level of 22 disparity in regional practice or local practices 236 1 that we have now. So that we are really fostering 2 efforts to get there. Again, George mentioned some 3 of the tools that are available within government. 4 Already organizations like CIOMS have prepared a 5 guideline for operating procedure for institutional 6 -- it's a work around the world. And those tools 7 are already available. So I'm not sure that we 8 would gain a lot by doing that. 9 Instead, we are trying to emphasize what 10 both the research community and the Office of the 11 Inspector General have called for, and that's 12 flexibility with accountability. We recognize that 13 institutions vary enormously in size, the way they 14 operate, and it's not just institutions also. 15 So as we move to a level playing field, we 16 have to consider that there's all the research, in 17 fact, more research done in the private sector 18 that's non-institutionally based. And so, again, 19 the key thing here is for everyone to understand 20 their responsibilities and take the actions 21 necessary through their own initiatives to meet 22 those responsibilities and expect to be held 237 1 accountable for doing so. 2 CHAIRPERSON MARSHALL: Sandy. 3 DR. CHODOSH: I'm a little bit dense as I 4 get older, but it's a little unclear to me how 5 avoiding looking at SPs and replacing it with 6 federal-wide assurances is going to help with the 7 problem for which SPs were designed, namely, the 8 institutions that do not do very much work, do not 9 have the kind of depth of staff and how does the 10 FWA improve that? 11 MR. GASPARIS: Good question, Sandy. 12 Actually, to give this overview in 15 minutes, I 13 couldn't go into detail with some of our thought 14 processes along the way. We feel comfortable 15 moving ahead because most of the research covered 16 by SPAs tends to be lower-risk research that's to 17 small business enterprise or innovative research 18 grants. And when most of this research involves 19 higher risk research, it involves a medical center 20 where the research is actually conducted. So, 21 there is some safety net already in the system 22 moving forward in that that research would be 238 1 reviewed by a more experienced IRB. 2 We found though in our past experience 3 that some of the research that we reviewed that was 4 minimal risk, however, these IRBs just don't get 5 it, or don't do as well of a job and we need to 6 reach out quickly to them to strengthen that IRB 7 system. 8 So I'm going to try to invite all former 9 SPA institutions to join rather quickly in our QA 10 initiative. We've already received many requests 11 for a QA program once it's released. But that's 12 the part that we want to attack pretty aggressively 13 and reach out to these smaller IRBs that don't have 14 as much experience to strengthen their operation. 15 We had to move forward in this direction, 16 however, because we were falling behind. We 17 couldn't keep up with the workload. It was just 18 too much to do. We had to overhaul our review 19 system to a more effective review system. 20 DR. KOSKI: I think also that we need to 21 recognize that spot approvals, kind of like spot 22 zoning, if you will, means that things may be okay 239 1 on the corner of Fifth and Vine, but, you know, 2 there's a lot of different corner operations that 3 need to be addressed. The focus in our efforts are 4 toward building a real system instead. And, using 5 the combined approach of systemwide education with 6 systemwide quality improvement efforts coupled 7 with, in the private/public partnership 8 accreditation as a means to establish that level 9 playing field, I think is the way to get to where 10 we need to be to have really a uniform safety net 11 that's tightly knit across the board. 12 So we are trying to put our resources into 13 that and, of course, to get there, we need to turn 14 to the private sector to really rely on and 15 collaborate with organizations such as Primer and 16 ACRP and a host of others that sort of crossed the 17 entire domain in order to begin to knit this 18 together. So that is where we are going. 19 DR. CHODOSH: I understand what you're 20 saying. I guess I have some concerns about how 21 long it's going to take to get that net up in place 22 -- the safety net. And, you know, I would hate to 240 1 see a lot of things falling through the cracks. 2 That's all. 3 CHAIRPERSON MARSHALL: Denyse, did I see 4 your hand up? No. Okay. 5 Jonathan. 6 DR. MORENO: In the spirit of Sandy's 7 comment, will we have the opportunity to see the 8 draft version of the FWA? 9 MR. GASPARIS: Yes 10 DR. MORENO: Will we have the opportunity 11 to see it before the next meeting, I guess is the 12 force of my question since -- 13 MR. GASPARIS: Yes. A little better than 14 that. In your book right now you do have the FWA, 15 its terms of assurance and IRB registration which 16 is currently in practice. You also have the draft 17 QA tool which was developed and released last month 18 -- released last month, developed over the past few 19 months. Either this evening or after this meeting 20 we will give you a copy of the draft. 21 DR. MORENO: Thank you. 22 DR. KOSKI: If I could just throw in one 241 1 more comment on this also. The way the new 2 assurance process is developed, by the way, allows 3 for smaller institutions, okay, that may not be 4 able to truly afford the really enormous costs of 5 running an effective human research protection 6 program to actually rely upon another organization 7 to serve the central part of that while they 8 maintain their own local implementation component 9 of that. So it's still respectful of the 10 individual site where it's being done. I believe 11 that as we go forward, as we see the system evolve, 12 okay, people will come to recognize that this 13 assurance is more than just a contract. It is a 14 promise. An assurance is a promise. And when you 15 promise the federal government that you're going to 16 do it according to a specific set of regulations 17 and realize that there are enormous consequences 18 for not keeping your promise to the federal 19 government, I think we'll begin to see a movement 20 toward reliance upon programs that can provide that 21 function in the most robust way with greater 22 efficiency and effectiveness. So this is something 242 1 that has to evolve. 2 However, under our new -- you'll hear also 3 about our expansion of compliance oversight 4 activities on a not-for-cause basis in a moment. 5 We will be reaching out to probably 70 or more 6 programs engaged in human research per month. 7 Okay. That's not four per year, or, you know, 8 whatever. It's 70 per month which is a very, very 9 different spectrum. And merely the fact that 10 people know that not only are they making a 11 promise, but that someone is going to be looking at 12 what they're doing to fulfill that promise in a 13 very active way provides a powerful incentive for 14 making sure you're doing it right. 15 CHAIRPERSON MARSHALL: Mark. 16 MR. BARNES: George, I wanted to ask you 17 about the QA process. It seems to me that based on 18 the form that you have here that what you're 19 calling QA is actually a form that's submitted by 20 the IRB to your office to determine the compliance 21 with a series of standards. And I wonder a couple 22 of things. One is, what's the line going to be 243 1 between sort of enforcement and QA since 2 institutions are voluntarily submitting this stuff 3 to you, and especially if some of their answers to 4 this are that they are not doing what they ought to 5 do, then how will that, or will that not be used by 6 the people on the compliance side? 7 And the second question is, this is an 8 observation for whatever good it's worth, the QA 9 traditionally in health care is done under a cloak 10 of confidentiality and that confidentiality is not 11 federal law, it's state-by-state law. And state 12 laws basically insulate the quality assurance 13 process from discovery during malpractice suits and 14 other kinds of suits. 15 With the specter of liability hanging over 16 IRBs and IRB members now because of the many -- the 17 multiple lawsuits that have been filed against them 18 in various of the controversies that have been 19 talked about today, it seems to me that there is -- 20 aside from what you are doing here, that if one 21 wants the -- if you guys want appropriately IRBs to 22 really have an internal quality assurance process, 244 1 then have you thought about what kinds of 2 protections would attach and about whether there's 3 maybe some room for some federal regulation here? 4 MR. GASPARIS: Excellent questions and I 5 didn't expand on our QA program to inform you of 6 our thinking because it's tough to do that in 15 7 minutes and I may not have time to -- 8 [Laughter.] 9 MR. GASPARIS: -- do it now. But we've 10 thought through all of these questions which you 11 pose right now and we are coming up with, I think, 12 answers that will allow an institution to trust us 13 they volunteer under the QA program to improve 14 their system without causing damage. So we are 15 going in to an institution to work in a very 16 collegial manner in which we will discover 17 deficiencies and point the IRB and the overall 18 institution of human subject protection system in a 19 right direction; point them to the regulation, show 20 them that they need to improve in this area and 21 share the positive experiences from other human 22 subject protection systems, other IRBs in which the 245 1 IRB under scrutiny can improve their operation. 2 So, if we see an effective system, we'll 3 share that with the IRB as a suggestion. 4 With regards to your question about 5 confidentiality, what we are looking towards is 6 having an exemption under FOIA where any 7 information collected under the QA program would 8 not be released. And we've made some significant 9 positive steps that we can gain an exemption under 10 FOIA so that we could keep the promise that we will 11 not release information collected under QA. We are 12 very sensitive that whatever information we collect 13 we're going to collect it in a manner in which we 14 could do our work, but would not be released to an 15 outside group. 16 CHAIRPERSON MARSHALL: Bob. 17 DR. R. LEVINE: I wanted to make a general 18 comment. What we are starting to do now is what I 19 thought the purpose of NHRPAC was when I agreed to 20 join it, whenever I agreed to join it. We are now 21 actually looking at the policies and practices of 22 OHRP. And I think that's the most important thing 246 1 that this committee can do. 2 I'm sorry that this is taken out of 3 George's 15 minutes, but -- 4 [Laughter.] 5 DR. R. LEVINE: -- but as we've heard from 6 our speakers so far, there's been any number of 7 issues that I would have brought up if we had 8 enough time to deal with them in detail. I think 9 Mark's question highlights the need for this. The 10 time to explore confidentiality of quality 11 assurance is not after you've got the program up 12 and running. And this is why I think NHRPAC 13 probably ought to be kept aware of what your plans 14 are with regard to the future. I think it would 15 have been helpful before you decided to recognize 16 CIOMS and Helsinki as good alternatives to Belmont 17 to have talked with this committee and you would 18 have heard some stories about Helsinki in 19 particular and CIOMS to a lesser extent is flatly 20 inconsistent with federal -- U.S. federal policies 21 and practices. And, you know, perhaps you might 22 have come to a different conclusion. 247 1 But what I want to put in a plea for is 2 for this committee to serve, as I thought it was 3 going to, as in a relationship to OHRP is say the 4 Advisory Council of NIMH serves to the program 5 staff at NIMH to discuss policy decisions and 6 strategies before they actually get out there. 7 One of my big concerns is that the recent 8 activities of OHRP have been interpreted variously 9 in the newspapers and by members of IRBs. When you 10 say you want your educational program to reach 11 people who serve on appointments and promotions 12 committees, and Mary Faith says, well, we're glad 13 you're reaching out to them, I'd be astonished if 14 any of them come to your educational program. 15 Investigators want to do, at this point they're 16 happy to take their one hour on the Internet and 17 get their certificate so they can submit their 18 grant. 19 These are things that I think could be 20 discussed at this committee which is made up of a 21 lot of people who have a lot of experience of a 22 type -- of various types that people at OHRP don't 248 1 have. I think we could help enhance not only the 2 activities of your office, but also the public's 3 response to it. 4 DR. MATHER: Could I just make a comment? 5 John Mather with the VA. Because I'd like to go 6 back to the FWA and we've been working with George 7 and OHRP to eliminate duplicate effort that 8 happened in the VA where we had our own assurance 9 and then there was the OPRR and the OHRP 10 assurances. I think over the last year our 11 experience in working with this pilot has been it 12 has in fact strengthened and simplified and made 13 more efficient. There was probably one downside 14 and that is, if you don't run your own IRB under 15 your own FWA, it will probably spawn another set of 16 guidances that you're going to need in a government 17 structure. 18 So if you use somebody else's IRB, you're 19 going to have to have some kind of agreement, MOU, 20 or whatever you want to call it, and certainly in 21 the accreditation program that the VA is sponsoring 22 through NAQUA, there's a requirement there that if 249 1 one uses somebody else's IRB that there is these 2 understanding in a government structure. 3 But it's gone one step beyond that and 4 very clearly there is no free lunch. And this 5 costs money. And so if you don't use your own IRB 6 in all likelihood, just like with commercial IRBs, 7 it's going to cost money. And I think somewhere in 8 this and Greg and I have talked a little bit about 9 this. Although it's not our responsibility in a 10 way to worry about the money, this is still a high 11 cost endeavor. And if you more into the other 12 areas George and I have taught about, the QA and we 13 are doing something similar in the VA, again, this 14 is no free lunch. 15 And the concern I have in some of this is, 16 the underlying issue that yet has got to be 17 addressed and that is issues like NIH indirects and 18 the other kinds of money that support this kind of 19 enterprise. It's terribly important the direction 20 we're going in, but I want to raise the issue that 21 this is no free lunch. 22 CHAIRPERSON MARSHALL: Thank you very 250 1 much. I think Bob wanted to respond to that, then 2 I have Elliot. 3 DR. R. LEVINE: Not respond to that, but 4 one thing that Mark's comment, one memory it 5 recalled for me that I wanted to make as part of 6 what I said earlier is that OHRP and its 7 predecessor OPRR have been perhaps unknowingly 8 exploited by people out there. One favorite trick 9 of plaintiff's attorneys is to file an anonymous 10 complaint against an institution and then have OPRR 11 or OHRP more recently go in there, conduct a full- 12 scale investigation and then they get access to all 13 of the records of this under Freedom of 14 Information. They're getting about $30 to 50,000 15 worth of free discovery, and then this is used to 16 form the basis of litigation against the 17 institution that was targeted with an anonymous 18 complaint which OHRP frequently finds is 19 groundless. 20 CHAIRPERSON MARSHALL: Elliot -- or, Greg, 21 were you going to respond to that? 22 DR. KOSKI: I just wanted to quickly 251 1 comment with respect to Dr. Mather's comment, that 2 certainly the issue of resources for human research 3 protection programs have not gone unnoticed nor 4 have some of the other issues that Bob brought up. 5 Indeed, we're working actively with both 6 NIH and with the budget office to find appropriate 7 ways to make sure that resources are directed 8 toward doing this job right. There are a number of 9 issues that we won't go into now in the interest of 10 time about how you categorize them as either 11 allocable, direct costs, direct costs, indirect 12 costs, administrative costs, special costs, it 13 doesn't matter. What we need to do is to make sure 14 whatever mechanism is used, and it may be a 15 creative mechanism, is such that it provides, you 16 know, the resources necessary to do the job, 17 recognizing that protection of human subjects, as 18 I've said many, many times is part of the research 19 endeavor. It's not just an administrative add-on 20 to that and we've got to look at it in that 21 context. 22 Dr. Baldwin at NIH has been instrumental 252 1 in trying to move this forward and I don't see 2 Wendy or Belinda here today, Belinda Seto, but they 3 are working actively on that. And I believe that 4 everyone recognizes that need. So we'll continue 5 to move forward with it. Thanks. 6 DR. DORFF: I'm a novice to all of this. 7 So forgive me if what I'm about to say is way off 8 base. Right. But two things. One is, there are 9 an awful lot of abbreviations that you've been 10 using -- 11 [Laughter.] 12 DR. DORFF: That -- 13 AUDIENCE PARTICIPANT: [Off mic.] 14 DR. DORFF: But you're creating a self 15 assessment tool for people who are not part of the 16 government. Right. And I think, you know, you 17 have to ask yourself -- I mean, there are two 18 places in here which you use an abbreviation that 19 you actually spell out the meaning of. That's 20 great. Do that. Okay. If you're going to do 21 that. 22 But, I mean, like in your presentation you 253 1 have one line in here, MPA, CPAs, SPAs, CAs, 2A, 2 A2s, NIAs eliminated. I'm glad for that. 3 [Laughter.] 4 AUDIENCE PARTICIPANT: [Off mic.] That's 5 all you need to know. 6 DR. DORFF: That's right. But the other 7 thing -- and then, also, in the form you refer to 8 -- I'm on questions 97, 98 -- for research 9 involving prisoners of the -- document IRB findings 10 is required under 45 CFR 46.305,306. I mean, I 11 think minimally you at least have to provide a copy 12 of that to any institution that is going to be 13 doing it, all right. 14 DR. KOSKI: Let me just say -- 15 DR. DORFF: And then the other thing -- 16 the other thing is, you have 128 questions here. 17 Right? I mean, more is less, to be very honest. A 18 good principle in education. It seems to me that 19 if you could pare this down to what you really need 20 to know for an IRB to be able to figure out, to 21 evaluate itself and to figure out what is -- you 22 know, what's going on, and only the very last part 254 1 of this deals with human subject protections. So, 2 I mean, if this is a quality assurance thing, I 3 take it for everything about the IRB and not just 4 human subject research -- right -- protections. 5 So, I mean, first of all, okay. But, I 6 mean, they should at least know what they're 7 getting into if they're doing this. That this is 8 not only for human subject protection, that this is 9 for other things as well. 10 But even for these other things, I mean, 11 if you had 20 questions rather than 128, it would 12 go much further. 13 DR. KOSKI: Well, I was just going to 14 point out that if there's anyone running an IRB 15 that doesn't know what 45 CFR 46 is, they shouldn't 16 be running an IRB. 17 CHAIRPERSON MARSHALL: Susan. 18 DR. KORNETSKY: Yes, Elliot, I just want 19 to say, you are a novice to it. I mean, I've had 20 an opportunity to look through this and for someone 21 who works in the IRB profession, a lot of it does 22 make sense. There may be some areas that it can be 255 1 shortened and, you know, they are obviously looking 2 for input, but it's a pretty complicated thing. 3 MR. GASPARIS: Elliot, I would like to 4 thank you for your comments. First of all, our 5 ears have grown a lot over the past eight months 6 and are continuing to grow. And perhaps the 7 biggest skill we are trying to improve on is 8 listening. So any comments you have about the 9 draft, please submit them to us and we'll consider 10 them very objectively and especially about 11 abbreviations. 12 The reason I did not explain in a 13 presentation what all those abbreviations were, it 14 was intention because I want to show that we're 15 moving from this complicated system to a much 16 simpler system. So, that accomplished my goal in 17 that you were confused. 18 [Laughter.] 19 MR. GASPARIS: That's what I wanted you to 20 experience. 21 DR. CHODOSH: Could I suggest that you 22 actually have an excellent quality assurance model 256 1 here. You have 128 questions if you'll only add to 2 it, yes, no, I don't understand the question. And 3 if you can reduce that latter category, you'll have 4 an excellent quality assurance model. 5 MR. GASPARIS: Thank you, Sandy. That's a 6 great suggestion. 7 With regards to the size of the tool, 8 we're soliciting feedback, we're trying to balance 9 two objectives here; to be as comprehensive as 10 possible, but because IRBs are so burdened, I don't 11 want to take up a tremendous amount of time site 12 visiting them and distracting them from their task 13 at hand in protecting human subjects. So we need 14 to balance the amount of comprehension that we can 15 gain of the system versus least amount of time that 16 we can do to assess them. 17 DR. KOSKI: I would just quickly comment 18 that the real purpose here, again, is quality 19 improvement. Not so much quality assurance. 20 Quality assurance is an auditing tool. Quality 21 improvement means you get a better product out of 22 it. And, of course, you have to make an assessment 257 1 before you can find where there are strengths and 2 weaknesses in order to fix the process, in order to 3 make it work better. 4 But the real emphasis here is on quality 5 improvement. And there are two needs basically. 6 One is to make sure that you're satisfying your 7 requirements under your assurance which means the 8 regulatory requirements, although we didn't want 9 that to be the focus, the rest of it is to actually 10 go beyond the minimal regulatory requirements to 11 try to help build a program. 12 And in setting up this kind of tool, it 13 focuses on a number of areas that may not be 14 immediately required under regulation, but it would 15 help prepare programs for achieving accreditation 16 within the private voluntary sector. So there 17 actually is a logic to it. 18 In fact, there are probably more than 128 19 specific points that you need to meet under the 20 regulations, but we don't need to go into all of 21 those right now. 22 CHAIRPERSON MARSHALL: Any questions from 258 1 our ex-officio or our public members and folks in 2 the audience? Any others for George? 3 DR. F. LEVINE: That sort of picks up on a 4 number of themes and something great that you just 5 made reference to when this is this at-the-moment 6 voluntary accreditation process in the private 7 sector, that is -- is likely to evolve and how much 8 and how are you thinking about kind of the 9 alignment between your ends of the process and what 10 will be this additional tier which each are under 11 resourced and somewhat partial. 12 DR. KOSKI: Well, the beauty of the 13 quality or, I'm sorry, of at accreditation process, 14 okay, is that it is something that is nonregulatory 15 in nature that actually allows sites to demonstrate 16 their commitment to achieving a standard of 17 excellence in their performance that can actually 18 serve as a plus in the marketplace, if I may use 19 that term loosely. Indeed, the pharmaceutical 20 industry has already stepped up and said, we 21 recognize the value of this. 22 In fact, if we only place our research at 259 1 institutions that have achieve accreditation for 2 their human research protection program, we are 3 going to be better off because we will have fewer 4 studies that are being thrown out because they 5 haven't been done right with respect to protections 6 of human subjects. So it actually, the whole 7 process works better that way. 8 We see the private voluntary accreditation 9 as an extremely powerful complement to the 10 government's regulatory activities. Because if we 11 have a database for instance that covers all 12 registered programs and we can cross-reference that 13 to a database of all accredited programs, well, if 14 you've got 80 percent that are accreditation and 20 15 percent that aren't, where would we most 16 productively devote our efforts toward further 17 improvements in the program? 18 I think you can see, in fact, there's a 19 logic to the way it all fits together. And, yes, 20 it will take some time to get there. It has to 21 grow. But that's the very reason why the very 22 first step that we tried to foster was to work with 260 1 the private sector in order to develop systems for 2 accreditation of human research protection 3 programs, again, focusing on the programmatic 4 systems issues rather than just on accreditation of 5 IRBs. 6 CHAIRPERSON MARSHALL: George, thank you 7 very much. 8 Kristina, Division of Compliance, welcome. 9 DR. BORROR: Well, thank you very much for 10 this opportunity to come talk to you today about 11 OHRP's compliance oversight procedures in general. 12 It's a great pleasure to be here. 13 Generally, I am going to talk to you today 14 about the activities in the Compliance Division and 15 some of the common areas of noncompliance that OHRP 16 identifies during investigations and some of the 17 underlying causes of noncompliance. Actually, I 18 don't know if I'm going to get to that last one. 19 OHRP's jurisdiction includes research that 20 is conducted or supported by the Department of 21 Health and Human Services and also research that is 22 conducted at an institution that has an applicable 261 1 assurance of compliance. And George told you a lot 2 about the assurance process. 3 Our compliance oversight activities 4 include compliance oversight investigations. This 5 is probably a lot of the bulk of the work that our 6 division does. We receive allegations of 7 noncompliance from a variety of sources including 8 people who have been subjects in research and 9 believe that they have been harmed or mistreated; 10 from investigators themselves; or people who are at 11 institutions who believe that there is 12 noncompliance going on; or from the public, and 13 even sometimes in reading the literature our own 14 staff sometimes identifies problems or potential 15 problems that we see in research. And then we 16 determine whether or not we have jurisdiction and 17 write a written inquiry to the appropriate 18 institute and those officials. 19 We receive from them a report from the 20 institution and relevant IRB documents and review 21 them very carefully. And this can take a long time 22 as some of you who have been on the receiving end 262 1 of an allegation may know. That we have additional 2 correspondence back and forth with the institution 3 often first telling them about questions or 4 concerns that we may have that arose from our 5 review of the material. We will sometimes talk to 6 them on the phone because sometimes that's a lot 7 quicker than going back and forth with letters. 8 And, very occasionally a site visit may be 9 warranted. And after all of this is done we 10 usually issue final determinations. 11 There are many possible determinations or 12 outcomes that can result from an investigation. 13 The one that everybody would like to see is 14 protections under that institution's assurance are 15 in compliance. 16 Another one that is very common is 17 protections under their assurance are in 18 compliance, but OHRP can recommend additional 19 improvements that the institution can make. And 20 another outcome is that we identify areas of 21 noncompliance and require particular corrective 22 actions. Also, we may identify noncompliance and 263 1 restrict the assurance pending corrective action. 2 Additional and more severe outcome is that 3 noncompliance is identified and the assurance is 4 withdrawn from the institution by OHRP. 5 In addition, even more strong outcome is 6 that we can recommend to appropriate department 7 officials or agency heads that either an 8 institution or an investigator can be temporarily 9 suspended or permanently removed from participation 10 in a specific project or that peer review groups be 11 notified of noncompliance prior to review of new 12 projects. 13 And this last one has never been done, but 14 that's that OHRP may also recommend that 15 institutions or investigators be declared 16 ineligible to participate in HHS research. This is 17 known as debarment. 18 I believe in the packet that you got are 19 some of the common findings that are made by our 20 office and these are common areas of noncompliance 21 that we identified. This can also be found on our 22 web site and I think that you'll find that it's 264 1 very helpful. These areas include all the areas 2 that IRBs are involved in and that researchers 3 interact with IRBs regarding initial and continuing 4 review, expedited review, unanticipated problems 5 reporting, changes to protocols, informed consent, 6 et cetera. I'm going to go into this in a little 7 bit more detail. 8 Some of the common findings that we make 9 regarding initial and continuing IRB review are 10 that the IRB receives insufficient information from 11 the investigator in order to make the 12 determinations that whether or not the research is 13 really in compliance. Also we sometimes find that 14 there is inadequate review, or that continuing 15 review is not substantive. There is also a very 16 common failure to conduct continuing review at 17 least annually. There is sometimes a lack of a 18 quorum, there is not enough people at the IRB in 19 order to actually vote on protocols, or a very 20 serious problem. Sometimes research is actually 21 conducted without ever being brought to the IRB for 22 review. 265 1 Some other findings regarding expedited 2 review are inappropriate use of expedited review 3 both for initial and continuing review, and also 4 for the review of changes to protocols or the 5 failure to advise the full IRB of expedited 6 approvals that were done by either a chair or an 7 IRB member. 8 We often see problems with informed 9 consent, both with the process and with the form. 10 The elements that are required under 45 CFR 46.116 11 are not often all there. Or it's sometimes 12 appropriate to include the additional elements at 13 116(b) and informed consent documents will 14 sometimes either underestimate the risks that a 15 subject may be exposed to or overestimate their 16 potential benefits which is a problem. 17 The language sometimes is very complex. 18 It has a lot of medical jargon that the average 19 subject wouldn't understand. And it sometimes 20 contains exculpatory language in which a subject 21 may appear to waive rights. There are also 22 findings that we make regarding IRB membership, 266 1 expertise and support, including lack of diversity 2 of the membership, lack of expertise for research 3 regarding children and a lack of a prisoner, 4 representative, or just insufficient understanding 5 of the regulations and a big one, a major one, is 6 inadequate resources for the IRB. 7 Common findings regarding their policies 8 and procedures and the findings they make include 9 inadequate IRB records and minutes, failure of the 10 IRB to consider what additional protections may be 11 needed for research involving vulnerable subjects 12 or to make required findings regarding research 13 involving children. Also, making required findings 14 regarding waiver of informed consent or 15 documentation of informed consent. And a very, 16 very common finding is just lack of appropriate 17 written policies. They may be doing the right 18 things, but they just don't have them written down 19 sometimes. 20 What are some of the underlying clauses of 21 noncompliance? Some of these are no-brainers, but 22 they are very common. One was addressed by Dr. 267 1 Cohen and that is inadequate education of IRB 2 members, the staff, and also the investigators. 3 It's also sometimes inadequate staff and resources 4 for the IRB and tied to that, just overburdened 5 IRBs. The IRBs, either one or a few, are just 6 reviewing too much research in too little time. 7 I think that's the end, and I'll take any 8 questions. 9 CHAIRPERSON MARSHALL: I'm sure that there 10 will be some. I have Bob, Sandy, Adil, and Abbey. 11 DR. RICH: I serve as the editor of a 12 major scientific journal. We have four categories 13 of responses that we get with submitted 14 manuscripts. The largest majority of manuscripts, 15 about 60 percent get a rejection letter; about 25 16 percent get a letter that says, "not acceptable in 17 its present form"; a small percentage get an 18 acceptable with minor revisions; and almost nobody 19 gets a clean bill of health. 20 I am trying to put that same kind of 21 notion into the context of your possible outcomes 22 of review and I'm wondering whether anybody ever 268 1 gets a clean bill of health as one outcome and the 2 one we hear about in the newspaper, of course, are 3 the ones that come, maybe not all the way to the 4 death sentence, but come as close to that as one 5 might come without having any -- and I'm wondering 6 if you can give me a sense of how that breaks down. 7 DR. BORROR: You're correct in that there 8 is always room for improvement. I certainly -- you 9 know, I haven't been in this office as long as some 10 others who are talking to you today, but I have 11 always been able to find problems. Sometimes we 12 just make recommendations. The most common problem 13 as I maybe mentioned is just the written procedures 14 and policies are just not there. And as I said, 15 they may be doing it. They just haven't written it 16 down in a way that gives enough details that you 17 understand what it is that they're doing and that's 18 probably the most common. And I can find it almost 19 every time. 20 You know, the more serious allegations 21 that we are very concerned about, you know, happen 22 less often. And it's not unusual to, you know, at 269 1 the end of the day, make some findings, but in 2 overall to say that the main allegation was not 3 substantiated. But very often they are and we can 4 always find room for improvement. 5 DR. RICH: If I can just follow-up on that 6 then. Provided that you're responding to a 7 specific allegation, I'm wondering how often your 8 finding of being in noncompliance relate to human 9 subject protections that are relevant to the 10 allegation of a problem as oppose to filling off a 11 long list of things that you might be able to check 12 off, did they do this, did they, did they -- you 13 know, whether a quorum and everything. Were all 14 the minutes properly recorded and -- 15 DR. BORROR: We try to get enough 16 information to be able to certainly address the 17 allegation. You know, we also do get information 18 -- we usually will ask for the policies and 19 procedures so that we can -- even though that might 20 not be part of the allegations and we do sort of 21 have -- I mean, it's not really a sort of a mental 22 checklist to be able to do that. But we 270 1 concentrate -- we do a lot of look to see that the 2 allegations themselves, but we also try to look and 3 see if the whole entire system for the protection 4 of human subjects is in place and appears to be 5 working. 6 CHAIRPERSON MARSHALL: Sandy. 7 DR. KOSKI: If I could just quickly 8 comment to that also. For too long, you know, the 9 whole human research protection process has been 10 viewed really as sort of an administrative burden. 11 in many instances rather than its real purpose. 12 And that's often reflected, but it's been 13 dramatically changing. Okay. We see it every 14 place we go, all kinds of places are really working 15 to, you know, make effective systems. Realizing 16 that this is -- it's critically important as part 17 of the foundation for doing the research 18 responsibly. 19 In most instances noncompliance is 20 symptomatic. It's a symptom of either a lack of 21 understanding, a lack of resources, you know, 22 sometimes a lack of commitment. Our office, 271 1 remember, our motto is "doing it right together" 2 and the emphasis on doing it right together, that 3 means we have a certain role and so do the 4 institutions that have to fill their 5 responsibilities, investigators and others. So I 6 think that we clearly work very, very hard to use 7 the tools of our office to try and get people to 8 fulfill their responsibilities appropriately. But 9 we also have to recognize that there are instances 10 where people are unwilling to do that, for one 11 reason or another and we try to make sure that 12 whatever actions our office takes are appropriately 13 measured and responsive to the concerns and the 14 risks that the situation might pose. 15 So it's something where the goal, again, 16 is one that is not focused on punishment, but 17 rather on working toward making the system operate 18 as it's supposed to for the protection of human 19 subjects. 20 DR. RICH: I would just say that it's 21 surprising to me that nobody seems to be doing it 22 right though. If what I'm hearing is -- you know 272 1 -- 2 DR. BORROR: I think that I would like to 3 emphasize here is there's always room for 4 improvement. And part of my job is to give 5 recommendation and guidance to help IRBs and the 6 human subject protections systems improve. 7 CHAIRPERSON MARSHALL: Sandy. 8 DR. CHODOSH: This is along the same line. 9 And I'm not really quite sure if I heard the 10 answer. If I were a member of the press sitting 11 here right now, and I walked away with this 12 document, I could write a tremendous indictment of 13 the whole system. And I don't think that that is 14 entirely true. I think that just as we're talking 15 about definitions of other things such as minimal 16 risks et cetera, we need to talk about what is 17 common. Now, you put common on all of those things 18 and I think that common significant, common 19 administrative, I think that we need to put some 20 definition on this of else it looks like no one is 21 doing the job right. And I concur with Bob is 22 saying. And I can't believe that. You know, I 273 1 know that there is no one who is perfect, and I 2 know that you're right. Everyone can improve. 3 That's life. But to put it in the tone of you an 4 always find something wrong is not really the 5 message that we should be hearing. We should be 6 hearing, most people are doing things right, I 7 would hope, but there are areas and these are the 8 kinds of areas and these are the kinds of 9 percentages, et cetera. Otherwise, I think we're 10 sending the wrong message. 11 DR. BORROR: I agree that there's no 12 numerator or denominator here. And I think that 13 the reason why this document was made public is to 14 be more of a guidance document to institutions so 15 that they can look and learn from the mistakes of 16 other institutions and to really look hard, you 17 know, at this whole quality assurance and quality 18 improvement process is taking that a step further, 19 but to see where other institutions have made 20 mistakes and look at their own institute and say, 21 ah, well, are we doing that too? 22 DR. KOSKI: Sandy, one thing that I think 274 1 is important to recognize is that for 30 years the 2 side of human research protections that's been 3 overseen within HHS and the others has been 4 basically a kind of a free-running process where no 5 one has really been looking, except for those 6 instances where something would pop up where there 7 was a complaint or something. It was a system that 8 was based primarily on trust. And it's very 9 interesting because if you contrast this 10 environment with what the corporate sponsors, you 11 know, have been faced with over the years which has 12 been a very strict regulatory structure with 13 auditing and everything else to enforce that, 14 there's a difference in the cultural approach. 15 And, of course, what's happened over the 16 last several years it that in the face of 17 increasing concerns about how well the system is 18 working, all of a sudden the eyes of the 19 regulators, okay, are being in a sense turned on a 20 system that has simply had a different cultural 21 orientation. 22 And I think that there are some 275 1 adaptations, you know, that's still going on and 2 some have certainly argued that there's been too 3 much focus on, again, regulatory compliance as the 4 goal which I for one have stated that many times so 5 that, again, I think that as we see a pendulum 6 swing back and forth, we'll begin to see, as we are 7 now doing across the board everyone, I think, 8 rising to the challenge to do things as best they 9 can. And our efforts are to support that. 10 It's very interesting to note that in 11 recent analyses done by FDA from their field 12 auditors, the numbers or the percentage of studies 13 that they audit now that have, you know, serious 14 deficiencies in critical elements of the kind of 15 research has actually fallen by more than 30 some 16 percent over the last year. So, again, that 17 heightened awareness and everything is there. But 18 I think your points are well taken. 19 You know, Adil and others have pointed out 20 today, you know, by and large a lot of committed 21 people who are really making the effort to do 22 things right and that's what we clearly want to 276 1 support. 2 CHAIRPERSON MARSHALL: I have Adil, I have 3 Abbey, I have Alan and then Elliot. Adil, and then 4 we need to move along. 5 DR. SHAMOO: You said invariably you found 6 that even the institutional policies just doesn't 7 have it in it to do certain things. And that 8 brings me to my question an hour ago. Why don't we 9 do this process prior to there is a complaint. 10 That is, OHRP review those institutional policies 11 and ensure that they are at least the minimal 12 existence of those requirement are in their 13 institutional policy rather than later on, you 14 know, hit them with a hammer. And I know for a 15 moment I'm sounding like Bob and Sandy, but forgive 16 me. 17 [Laughter.] 18 DR. KOSKI: Adil, again, to emphasize the 19 point that we've been saying many, many times, when 20 you make a promise that you're going to protect 21 human subjects and have an effective program to do 22 that, you make the promise. You know, if people 277 1 would like to see government regulators come in and 2 review everything, okay, that's an approach that 3 can be taken. And many have suggest that that's 4 the approach that should be taken. 5 We, in fact, believe that a different 6 approach, one that allows institutions to 7 demonstrate their responsibility and their 8 initiative to do it on their own, okay, is a more 9 productive approach. The key thing about the 10 quality improvement program, all right, is that it 11 fosters that kind of self evaluation. You can look 12 and see yourself. If there's anyplace in the 13 country doing human research and has a human 14 subjects protection program that hasn't done that 15 already, I can only ask, why not? Why not? What 16 are you waiting for? Okay. Because if you've made 17 the promise, it's time to act on that. Okay. So I 18 think it's the initiative that they have to bring 19 forward. 20 DR. SHAMOO: Can I give you their 21 perspective since I served with one of those 22 institutions more that an one, as a matter of fact. 278 1 And I quote/unquote, help them once in a while. 2 They do not know sometimes what you are thinking, 3 what you want. They do not know. I see Sandy 4 shaking his head. We don't know exactly how you 5 are interpreting these things. Sometimes they are 6 -- and you know me. I'm not on their side, but 7 really I feel for them sometimes. 8 [Laughter.] 9 CHAIRPERSON MARSHALL: We're making lots 10 of history here today, Adil. 11 [Laughter.] 12 CHAIRPERSON MARSHALL: Those of you who 13 are standing there are a lot of seats up here on 14 the side. If you would like to sit, please feel 15 free. 16 Abbey, Alan and Elliot and then we need to 17 move along. 18 MS. MEYERS: I'm wondering whether you 19 think that the penalties that are available to you 20 are adequate? It seems to me that sometimes you 21 use a cannon to kill a mosquito and you have to, 22 you know, so many times shut down a whole 279 1 university rather than -- if you had, for example, 2 the ability for civil monetary penalties or 3 whatever, would that be better? Something. We 4 could target the investigator rather than the whole 5 institution. 6 DR. KOSKI: We would never use a cannon to 7 swat a mosquito. As I said earlier, the actions 8 taken in the compliance mode by our office are 9 actions that are specifically directed to be 10 appropriate to the situation encountered. We have 11 enormous flexibility as Christine already mentioned 12 to target activities toward a specific 13 investigator, a specific project, or a specific 14 component of the IRB process. To a section of 15 research, to the entire institution. I think there 16 are a number of tools there. And so certainly what 17 our office has been trying to do again is to -- if 18 an action is required, to try and make sure that 19 that action is appropriately measured to the 20 situation to avoid what you might call collateral 21 damage and to avoid exactly this problem. So, you 22 know, I can make it very clear to everyone that 280 1 that's the way our office works. 2 With respect to the civil monetary 3 penalties, this was an idea that was actually 4 floated a year or more ago when Secretary Shalala 5 talked about various initiatives. It was an 6 initiative that I think recognized that in a 7 situation where monetary incentives may lead to 8 misconduct that monetary penalties may be an 9 appropriate remedy for that. While many still hold 10 to that, I think that the reception that the notion 11 received in Congress, the first go around was such 12 that no one has continued to maintain a high level 13 of enthusiasm for that particular approach. I 14 think we may hear more about that, though, when the 15 General Accounting Office speaks to us tomorrow 16 afternoon. 17 CHAIRPERSON MARSHALL: Alan and then 18 Elliot. 19 DR. FLEISCHMAN: I guess I have two 20 questions, one easy and one perhaps impertinent. 21 The easy one is really to ask how you and George 22 get along? That is to say -- 281 1 [Laughter.] 2 DR. FLEISCHMAN: -- you know, how close 3 are those two offices? I mean, we talked about 4 trust this morning and the academic community, 5 you've gotten the academic community aware of the 6 Office of Human Research Protections and the public 7 aware of the office. And you are now asking the 8 academic community to voluntarily get involved in 9 quality improvement which I happen to think is a 10 marvelous thing to do. And yet you've got this 11 other arm called compliance that does have multiple 12 potential negative consequences for the academic 13 community. And in looking at that quality 14 improvement form, it's not a lot different than 15 your review of an organization. 16 So, what should I tell the dean? That's 17 the first question. 18 And the second question is, we are really 19 -- we're discussing all of this in the abstract and 20 it strikes me that we have a very concrete example 21 in our midst with lots of public information 22 available about that example. That is the Hopkins 282 1 example. And I wonder if you could share with us 2 the process by which the Division of Compliance 3 went through in making the determination that it 4 made about its ultimate response to the university. 5 DR. BORROR: Well, I can't really -- I'll 6 take your first question. There is a lot of 7 interaction between the divisions within OHRP. As 8 I said, there is always room for improvement. As 9 far as the quality improvement part of this, and 10 Greg may correct me if I'm wrong here, but we want 11 to set a sort of a firewall in those -- you know, 12 the question about whether or not this information 13 is obtainable under the Freedom of Information Act, 14 and so forth, that institutions can feel free to, 15 you know, sort of air their dirty laundry so that 16 they can get improvement. That said, I think that 17 if we found like really serious problems and, you 18 know, there was concern that human subjects were at 19 risk at a particular institution we would have to 20 ask, I believe. Do you agree with that? 21 DR. KOSKI: Sure. Again, since George 22 isn't up here, I'll speak sort of on your behalf. 283 1 The goal here is to conduct the quality improvement 2 activities in what we call safe mode, okay. Fully 3 collaborative, open, exchange of information with 4 the understanding just as if you were in the 5 emergency room taking care of, you know, kids. You 6 know, when you have a kid come in who has obviously 7 been potentially abused, you have a certain 8 responsibility to act. I think that within the 9 quality improvement mode the expectation would be 10 that if a situation of such severity was 11 discovered, which I think in fact is unlikely, that 12 the institution would voluntarily sort of take that 13 sort of action. 14 The whole quality improvement program is 15 one that's voluntarily based. But people have to 16 understand that while that's going on in a 17 voluntary mode, there is running in the background 18 a separate subroutine called "compliance oversight" 19 that will include not only for-cause site visits, 20 but also an expanded array of not-for-cause 21 surveillance visits. So that if people are 22 unwilling to do what they need to do in a voluntary 284 1 fashion in order to make the program effective, 2 then it may become necessary to resort to a 3 compliance initiative. But I would hope that that 4 would not be the case. I can tell you that we 5 already have a waiting list of people volunteering 6 to have our teams come and conduct quality -- you 7 know, improvement visits with them. And similarly 8 they are already -- there's a waiting list for 9 people saying that they want to get in line for 10 accreditation as well. So I think it demonstrates 11 again the commitment from most places to really try 12 and do this in a very responsible manner. What we 13 want to do is support those efforts and basically 14 reserve compliance enforcement activities for those 15 who are unwilling or unable to do so. 16 CHAIRPERSON MARSHALL: Elliot. 17 DR. DORFF: Greg, that was a very good 18 lead in to the point that I was about to make which 19 is that I'm not used to the process of accrediting 20 IRBs. But I am used to the process for accrediting 21 universities because I have been a provost and on 22 and all of that and have gone through accreditation 285 1 of our university a number of times. And it's a 2 very long process and all of that, but it's a very 3 important process, truthfully, for universities. 4 And there, first of all, it doesn't happen on the 5 basis of allegations which, frankly bothers me, 6 because you could sort of get the sense that 7 somebody is, you know, relaying a secret whether 8 that person is identified or not, and, you know, 9 questions of rights of defense and all of that. 10 And I think -- I mean, you are probably -- 11 from what you've just said, you're overwhelmed 12 already. But what you may want to look toward the 13 accreditation of universities model as a different 14 way to do it. That is, where either your office or 15 an association of IRBs of some sort or another, 16 does this on a regular basis, every whatever, every 17 three years or something, there is a visitation 18 from this association to review the processes that 19 are going on in this particular IRB with the 20 intention of identifying those things which the IRB 21 is doing terrifically well and those places where 22 there might be room for improvement. In the cases 286 1 of universities, they have the ultimate, you know, 2 ability to either put the accreditation -- well, to 3 discredit them altogether or to say that your 4 accreditation is not going to be for six years, 5 it's going to be for three, and it will be 6 conditional on certain kinds of things and so on. 7 And even though that's not a government agency, it 8 has real power because if you're not accredited, 9 you're not going to get students, you're not going 10 to get grants, you are not going to get a whole 11 variety of other things. 12 And when I think that, you know, if it 13 were independent of your office, then you wouldn't 14 be overwhelmed to the extent that you are, in doing 15 this kind of thing, but even if you were to do 16 this, in other words, if you were to have -- you 17 know, get more people than the 47 and do this not 18 on the basis of allegations, but on the basis of a 19 regular kind of review process, I think people 20 would be -- well, first of all, they would be 21 helped by it as universities are helped by it. 22 And, aside from that, it would be everybody's in 287 1 the same boat. It would literally be doing it 2 together. 3 DR. KOSKI: Elliot, I refer you to the 4 report issued by the Institute of Medicine that we 5 had commissioned, it was issued last April called 6 preserving the public trust, accreditation of human 7 research protection participant programs where 8 those issues have been developed in really 9 elaborate detail. And, indeed, what you are 10 suggesting is exactly the program that is already 11 moving forward. There are two organizations that 12 are currently engaged in, or at least getting ready 13 for actually conducting the accreditation in the 14 private sector. One of those is the National 15 Council of Quality Assurance which has a contract 16 with the Veterans Administration to conduct 17 accreditation of all of the VA's human research 18 programs. 19 The second is a group called the 20 Association for the Accreditation of Human Research 21 Protection Programs which is now a private, not- 22 for-profit independent corporation entity that was 288 1 established with seed money from a number of 2 professional organizations through an effort that 3 was spearheaded in part by both Primer and the 4 Association of American Medical Colleges, but with 5 buy in from the CASA, a whole host of organizations 6 and FARMA with exactly this notion in mind: 7 You can establish a level playing field of 8 excellence rather than one based on minimal 9 regulatory requirements that actually provides a 10 positive recognition of the accomplishments that 11 can be rewarded rather than punished. It is 12 totally unrelated in any way to the compliance 13 oversight activities of our office. It's a private 14 complement to the processes that go on within 15 government. 16 CHAIRPERSON MARSHALL: I'm sorry. Thank 17 you. We need to move on, we're behind. But I want 18 to second that remark that Greg just made and say, 19 for committee members, probably reading at least 20 the executive summary of that report should be 21 required reading for all of you. This should be 22 part of your background knowledge as members of 289 1 this committee. It's superb work. So I commend it 2 to you highly, and it's available from the 3 Institute of Medicine on their web site. 4 I will ask Kate, we will get them for you. 5 We will have a copy for all of you because it's 6 tremendous work. 7 Thank you very much, Kristina. 8 And Greg is not suffering from an identity 9 crisis, but he will be Melody Lin for the next few 10 minutes. 11 DR. KOSKI: I will be very quick on this. 12 Melody couldn't be here today. She's back holding 13 down the fort as any good deputy would under these 14 circumstances. And so I actually offered to sort 15 of fill in for her on just a very quick sort of 16 update on where things stand with the new office 17 for international activities. Clearly, human 18 research is increasingly global in its scope and 19 conduct. And it's brought a number of issues to 20 the fore. Many of those, by the way will be sort 21 of addressed in an upcoming report from the Office 22 of the Inspector General of HHS. They were also 290 1 addressed in the recent NBAC report on 2 international clinical trials. I should point out 3 though that while those deal primarily with 4 clinical trials, there's a whole issue of non- 5 biomedical research that also goes on, on a global 6 basis that we need to keep in mind also. But we 7 are now seeing around the world, organizations such 8 as the global forum on bioethics, the European 9 forum on good clinical practices, the World Health 10 Association, the World Medical Association, the 11 CIOMS which is the Council of International 12 Organizations of Medical Societies, I believe -- 13 Medical Sciences. Yes, thank you. -- and others. 14 There are also organizations within many 15 countries such as Canada, India, Peru, the European 16 Union, China, Japan, a whole host. We are 17 beginning to see a nucleus of people who are 18 committed toward working toward a more harmonized 19 world with respect to the review and the conduct of 20 human research. I think there is a sense that 21 where standardization is possible and appropriate, 22 that might be a good thing to achieve, but 291 1 recognize that this is a very complex world we live 2 in. So that harmonization is sort of one of the 3 buzz words. 4 And we've seen that very effectively done 5 in the International Committee on Harmonization's 6 Good Clinical Practice Standards that now allow 7 data that's collected in clinical trials from 8 various countries to actually be used in support of 9 the drug approval process in multiple countries. 10 One of the other key words is building 11 capacity so that we -- some countries have more of 12 a system in place than others. Occasionally though 13 we have research that is intended to be done in a 14 culture or a country where there basically is no 15 infrastructure or system in place for either 16 overseeing or conducting the research. And where 17 there are instances of exploitation where people 18 who are serving their own interest rather than 19 those of research subjects, sort of, those are the 20 kinds of things that have caught some of the 21 attention, fortunately they are few and far 22 between. But, nevertheless, it's an area that has 292 1 raised concerns so we see this going forward. 2 Our Office of International Activities is 3 working very closely with the Fogarty International 4 Center at NIH, the FDA, our Office for 5 International Refugee Health as well as the various 6 federal agencies such as USAID and others that 7 actually are engaged in the global community. CDC 8 has been instrumental in that is. So that our 9 office is not so much to create a new federal 10 bureaucracy for the oversight of international 11 research activities, but rather to serve as a 12 coordinating center; a focal point for bringing 13 together and fostering activities that will 14 actually help to ensure that any research that is 15 done in the global community is done in an 16 appropriate manner with the highest scientific and 17 ethical standards. 18 We previously discussed some of the issues 19 around the Declaration of Helsinki. Again, that 's 20 an ongoing debate, but the World Medical 21 Association has established a committee to actually 22 look into some of the various issues that have been 293 1 raised, not only by our department, by this 2 committee, but also by other organizations and 3 groups around the world. I think this is going to 4 be something that's going to be on the front burner 5 now for this next decade as the world again comes 6 closer and closer together and gets smaller and 7 smaller. 8 I'm sorry that Melody couldn't be here 9 today, but if I can answer any questions on her 10 behalf, I would be happy to do so. 11 CHAIRPERSON MARSHALL: Any questions? 12 Abbey? 13 MS. MEYERS: All this attention on these 14 foreign studies. It seems to me that they didn't 15 get any attention at all until the Washington Post 16 did its expose. I'm wondering why no attention has 17 been paid to this? 18 DR. KOSKI: Abbey, I respectfully would 19 say I don't think that's true. I think that just 20 was one of those things that because it happened to 21 be a five part series or six part in the Washington 22 Post, it did capture a lot of attention that might 294 1 not otherwise have been there. But the concerns 2 have clearly been sort of rising within the 3 scientific community then the international 4 community and it's just eventually you get enough 5 critical mass that you begin to tackle some of 6 these things head on. So it's been there. It's 7 not going to go away. And we'll continue to work 8 on it. 9 CHAIRPERSON MARSHALL: Bob. 10 DR. R. LEVINE: I wanted to say that 11 there's been a lot of attention given to 12 international research since 1953 when the World 13 Medical Association first formed its ethics 14 committee and charged it with the responsibility to 15 develop what we now call the Declaration of 16 Helsinki. 17 CIOMS wrote its first international 18 ethical guideline in 1982. There has been a frenzy 19 of activity or a frenzy of attention of journalists 20 to the international matters ever since there was a 21 publication in the New England Journal accusing 22 people who ran the placebo control trials the short 295 1 duration of AZT having done something unethical on 2 the grounds that it violated the Declaration of 3 Helsinki. So there's been a lot of activity there. 4 I wanted to respond to something Alan 5 Fleischman raised earlier and that is that our 6 discussions in general have been at a level of 7 abstract generalities. I think many of us sitting 8 around this table could easily provide you with 9 concrete examples of specific issues that have been 10 problematic. 11 I can think of -- I mean, as we've been 12 talking, I can think of several dozen, but I've 13 held back on mentioning them because many of them 14 are attached to specific people and there's no need 15 to create public embarrassment, so I'll just 16 mention one that came up that was already mentioned 17 in the public forum at the meeting Greg and I went 18 to at the University of Illinois in Chicago where 19 somebody reported from the Veterans Administration 20 that they had been through an experience with this 21 accreditation group, the NCAQ. 22 And they had been advised that the 296 1 regulations require that the minutes of the meeting 2 show that who was in the room from minute-to-minute 3 and any time somebody left the room, you had to 4 record what time they left and when they came back, 5 you had to record what time they came back. And 6 this was explained as being required by regulations 7 because there was no other way to be sure that any 8 particular protocol was discussed when somebody 9 whose primary interests were in some area other 10 than science was in the room. 11 That's the sort of excess -- that's the 12 sort of thing that's creating great alienation 13 between the IRB world and the people who seem to be 14 acting on behalf of the federal government in the 15 educational and accreditation arena. These others, 16 you know, like the show used to say, there's 8 17 million stories in the naked city, this is just one 18 of them. 19 DR. KOSKI: Bob, I would just like to sort 20 of note -- go on record as someone who actually 21 chaired an IRB for a long time, as did you, that I 22 am personally painfully aware of a number of the 297 1 burdens that are imposed by the process. That's 2 one of the reasons why as part of sort of our 3 promise and our remodeling effort in going forward 4 we focused on things such as the SUEE task force 5 that I mentioned earlier where we realize that 6 there are probably real opportunities to move away 7 from these kinds of detailed procedural 8 requirements that may not be serving our best 9 interests. 10 But, again, one of the points, I mean, to 11 the extent that we can identify those and find ways 12 to basically get to the things that really serve 13 the purpose of protecting human subjects and then 14 implement those, we would be -- I think that would 15 be a good thing to do. I would also say though 16 that it's very difficult to do things that may be 17 perceived as in some way weakening the protections 18 process from a position of skepticism as to whether 19 or not the system is working in the first place. 20 So we need to help shore up a foundation 21 of trust and all that. As we go forward the SUEE 22 task force will be starting this fall and my hope 298 1 is that we'll have not only your several dozen, but 2 even more suggestions that we can identify as 3 opportunities to move forward to improve the 4 process. 5 CHAIRPERSON MARSHALL: A final question 6 from the committee for Adil. 7 DR. SHAMOO: Yes, could we just have a 8 copy of the slides of Dr. Borror? Because they're 9 not in package and will be very helpful for our own 10 education. 11 CHAIRPERSON MARSHALL: Anyone in the 12 audience who would -- 13 [No response.] 14 CHAIRPERSON MARSHALL: All right. Then 15 let me introduce Irene Stith-Coleman who is 16 director of the Office of Policy, Planning and 17 Special Projects. It sounds to me as though that 18 means she is head of everything and up there 19 somewhere in the pantheon with the first lady of 20 the admiralty. Welcome, Irene. 21 Dr. STITH-COLEMAN: Good afternoon. I 22 would like to also say that I appreciate being 299 1 invited to speak to you this afternoon. I'll be 2 brief, I promise. 3 Greg mentioned that there is an Office of 4 Policy, Planning, and Special Projects. We have a 5 total of three people including myself. In 6 addition to me there is Susan Zulo. Susan would 7 you stand? 8 And Cliff Sharkey who is not here. In 9 addition, Ana Beton, stand, has been very helpful 10 on a number of things that we're working on as 11 well. 12 Susan has been leading the effort with 13 respect to the SUEE task force. And in additional 14 to the SUEE task force, we are also involved in a 15 range of other issues including special panels that 16 are being created for special areas of research 17 including research involving prisoners and 18 children. And I won't go into that today. 19 I thought that what I might do for about 20 the next five minutes is talk to you about a 21 proposed final rule dealing with Subpart B because 22 that is, in fact, one of the key things that the 300 1 Department has actually published. And the 2 important thing about that is that there is still 3 time for public comment. And in light of this 4 morning's session in which there was discussion 5 about parental informed consent with respect to 6 adolescents, I thought that one of the 7 modifications that's being proposed in Subpart B is 8 quite relevant to that discussion. 9 You do have a copy of the proposed rule 10 that was published on July 6. And what I thought I 11 would briefly do is talk about the three 12 modifications that are being proposed. And just 13 add some context to that proposed rule, what is 14 doing is proposing to make some changes in the rule 15 that was published on January 17th, 2001. That 16 effective date of the January rule was supposed to 17 be March 17th of 2001. 18 Oh, I see some degree of confusion. The 19 rule published in January of 2001 had an effective 20 date of March 17th. However, the new 21 administration on February -- I think it was 22 February -- published a notice indicating that 301 1 there would be a delay. And this was part of the 2 Administration's assessment going back, I believe 3 it was 90 days to look at the regulations that then 4 had come into effect with the prior administration. 5 On May 18, the effective date of the 6 January rule was further delayed for 180 days. And 7 at that time it was indicated that several 8 modifications, three, would be made. And in the 9 July 6th proposed rule that you have in your 10 packet, those are the details of -- it contains the 11 details of the three modifications. 12 And without going into detail. The first 13 modification has to do with the definition of 14 fetus. What it is proposing to do is to modify the 15 definition of fetus so that it describes only the 16 stage prior to delivery. The Department believes 17 that using the term "fetus" only for those fetuses 18 that have not been delivered is more in keeping 19 with the ordinary meaning of what that word means. 20 That's the first modification. 21 The second in line with that, there is 22 also a proposal to add a new term "neonate" to 302 1 describe an infant that has been delivered but has 2 not yet been determined to be viable. The 3 modification would not change the regulatory 4 framework. 5 The second modification that's being 6 proposed in the July 6th proposed rule is to 7 require parental consent when the father is readily 8 available in federally funded research that's 9 directed solely at the fetus. In the case of 10 research that's directed at the mother or mother 11 and fetus, the mother still retains the right to 12 provide informed consent. 13 The third modification is a clarification 14 that fetuses of uncertain viability may be 15 subjected to greater than minimum risk only if the 16 research is intended to enhance the probability of 17 survival of that particular fetus. So those are 18 the three sets of modifications. 19 In terms of the process, the public 20 comment period goes from July 6th up until 21 September 4th. I encourage each of you to the 22 degree that you can express your rights as public 303 1 citizens to provide public comments. And the 2 public comments should be sent to me. The 3 specifics are in the proposed rule in terms of the 4 address a well as the e-mail, as well as my phone 5 number. 6 With that, I'll stop and take questions if 7 there are any. 8 CHAIRPERSON MARSHALL: Do we have 9 questions? Jonathan's hand is up. 10 DR. MORENO: Could you go over that 11 parental consent modification again? I'm afraid I 12 missed that. 13 Dr. STITH-COLEMAN: The parental consent 14 modification proposes that in cases in which the 15 research is directed solely at the fetus, parental 16 consent would have to come from both the mother and 17 the father, unless the father was not readily 18 available. 19 The difference with respect to how this 20 modification differs from the January 17th rule is 21 that within the January 17th final rule, the 22 parental consent need only come from the mother. 304 1 DR. MORENO: Alan, maybe you can help me 2 out. A long time ago, when we were talking about 3 076, we stumbled -- as you mentioned this morning 4 -- on the paternal consent requirement. How does 5 -- I believe there already is a paternal consent 6 requirement; isn't there? For -- 7 Dr. STITH-COLEMAN: There is. There is. 8 Yeah. One of the issues, my understanding, that 9 led to the January 17th rule was lack of clarity in 10 terms of practice on the part of a lot of IRBs in 11 terms of how the current regulations were 12 interpreted. 13 DR. R. LEVINE: But that was not an 14 example of lack of clarity. They were quite clear 15 on the point that you required the consent of both 16 the father and the mother. And when the specific 17 complaint during the 076 trial was that many people 18 -- and I was one of them -- thought that it would 19 have been appropriate to give the mother the sole 20 authority to decide whether or not she would enroll 21 in a placebo controlled trial of something designed 22 to protect or prevent transmission of the virus 305 1 from her to the fetus. 2 What you are doing now, it seems to me, is 3 taking the side against the protestors including 4 all the women. It sounds that way. 5 DR. KOSKI: Actually, no, I don't think 6 so. Because in the instance of the 076 trial where 7 there was the potential for benefit for both the 8 mother an the fetus, under those conditions there 9 would still be under the newly proposed rule it 10 would permit the mother to be the sole 11 decisionmaker in that instance. 12 Under the current administration's 13 policies, there is an expressed interest in 14 promoting the role of the father in a family unit 15 and it's in the context of promoting that that, you 16 know, the integrity of the sort of the family 17 process that they felt that this particular 18 revision to the proposed rule would be more 19 appropriate. 20 DR. R. LEVINE: Let me respond. This is 21 not the proper place to debate that subtlety. But 22 I don't think that anyone in the field of dealing 306 1 with HIV would attempt to pretend that the purpose 2 of the O76 regimen was to provide a therapeutic 3 benefit for the mother. In fact, some people 4 protested that pregnant women were the only adults 5 in the United States who would get a single anti- 6 retro viral that everyone else got combinations and 7 because of this it appeared that the woman was 8 being treated, and I forgive the infelicity of this 9 term, as mere fetus containers. Because they were 10 not being attentive to her needs. If they were, 11 they would have given combination therapy. 12 Well, I can only say that there's an open 13 period for public comment and we would urge anyone 14 who chooses to comment on the provisions of the 15 proposed final rule to do so. 16 DR. KOSKI: I'm trying to make the point 17 that the time to consult this committee is before 18 you made a commitment in writing in the public 19 forum to perhaps profit from some of the advice the 20 people on this committee with its various types of 21 expertise could offer. 22 CHAIRPERSON MARSHALL: Mark. 307 1 MR. BARNES: Since this is open for public 2 comment, could this be something that's referred to 3 the children's subcommittee for Alan and others to 4 comment on? That's one comment. 5 The other comment is on a lighter note 6 since this is a very weighty topic. I do want to 7 tell you that you can get away with calling this 8 group your task force SUEE like in New York and Los 9 Angeles, but I want to tell you where I'm from -- 10 [Laughter.] 11 MR. BARNES: -- I live down a little dirt 12 road in Alabama, that's the way that my great 13 grandmother called her pigs. 14 [Laughter.] 15 MR. BARNES: So just be careful. 16 DR. KOSKI: Mark. Thank you. I've 17 actually raised that point. Where I grew up in 18 Ohio that was also the way we called pigs. And, 19 you know, the greater caution, I think, was 20 expressed to me shortly after President Bush and 21 his team, you know, got here. Because SUEE is also 22 the call of the Arkansas Razorbacks -- 308 1 [Laughter.] 2 DR. KOSKI: Nevertheless, I think the 3 goals are laudable and I hope that the acronym 4 doesn't stand in the way of progress. It's our 5 intent to take the recommendations from the SUEE 6 task force which will be a brainstorming session 7 that will broadly consult with the research 8 community every stakeholder as well -- I mean, you 9 know, across the board and bring those 10 recommendations to this committee for their input 11 so that we get a real sense of, you know, an 12 okayness as we go forward to try to implement those 13 suggestions. 14 The last comment I might make around this 15 issue. We've heard Irene say that her office has 16 three people and we've heard Jeff say his office 17 has five people and so on, I think it's important 18 to recognize that the overall system for protection 19 of human subjects is one that is broadly 20 distributed. Our office is essentially one office 21 that serves a very important coordinating role in 22 terms of implementing the government's regulatory 309 1 authorities and so on. But, indeed, the whole 2 system is one that involves some 4 to 6,000 3 institutional review boards with -- if you multiply 4 that out, it's probably somewhere on the order of 5 40 to 60,000, you know, IRB members and other 6 people participating in this. And, it's, you know, 7 as I said, a distributed system where much like the 8 Air Transportation Safety System, you have people 9 working in role all over the country, around the 10 world that are all trying to make things safe for a 11 good reason. I think that's the concept that we 12 are trying to bring toward human research 13 protections as well, which is why we've placed so 14 much emphasis on working together. So I would 15 suggest that we not see human research protections 16 as simply, you know, 47 designated FTEs within the 17 Office for Human Research Protections, but 18 recognize that there are people both throughout 19 government and out there in the real world who 20 share in these goals and responsibilities. 21 CHAIRPERSON MARSHALL: I'm going to take 22 that prerogative, the chair and ask a question of 310 1 Irene and maybe perhaps have it be the last 2 question since we are behind time now. 3 Irene, what do you see? I think Bob's 4 remark does beg the question of the relationship 5 between the SUEE task force and this committee, and 6 how do you see that relationship playing out? 7 Dr. STITH-COLEMAN: Greg, do you want to 8 answer that? 9 [Laughter.] 10 DR. KOSKI: Well, we look to this 11 committee as, again, a source of advice. When that 12 advice comes to us, then it's our responsibility 13 within, you know, government to use it, in our best 14 judgment to develop appropriate guidance, rules, 15 regulations, legislation, whatever is necessary to 16 accomplish the goals so that, again, this committee 17 is a critically important advisory committee. To 18 the fullest extent possible, we would like to get 19 that advice ahead of time. I think given the 20 intricacies or complexities of government, or the 21 realities also, that that's not always possible, 22 but to the extent possible, we hope to do that. 311 1 CHAIRPERSON MARSHALL: One last question 2 of Alan and then we'll move on into our break. 3 DR. FLEISCHMAN: I think this would be a 4 question for information. I was wondering if Dr. 5 Stith-Coleman, you or someone in your office, has a 6 grid which would share with us the regulations as 7 they were extant before January, the regulations 8 that were in fact proposed in January and these and 9 how they are different. 10 It's my understanding that these are quite 11 different than January's regulations and have 12 implications that are far different from those. 13 And I just wondered if you had those arrayed and if 14 you could share those with us. 15 Dr. STITH-COLEMAN: I know I have the last 16 two. And I would think that someone in OHRP would 17 have the first one. So, probably yes. 18 CHAIRPERSON MARSHALL: Thank you very 19 much, Irene. 20 And Kate has one last word and then we 21 will take a ten-minute break. 22 MS. GOTTFRIED: I just want to mention to 312 1 the committee that some of you may not have 2 complete Children's Report to Congress, and if so, 3 just let Tony know outside, and if she's not there, 4 let me know. Because some of the books seem to be 5 complete and for some reason some of them aren't. 6 And it's hard for us to figure out which ones are 7 which. So just let us know if anything in your 8 briefing book is incomplete and we'll make sure you 9 get a full copy. 10 CHAIRPERSON MARSHALL: And those of you 11 from OHRP, thank you very much for bringing us up 12 to speed this afternoon. 13 [Applause.] 14 CHAIRPERSON MARSHALL: We will reconvene 15 at ten after four. 16 [Brief recess taken at 4:00 p.m.] 17 CHAIRPERSON MARSHALL: Actually, before we 18 begin with our agenda, we have an announcement that 19 may be of interest to those of you in the audience 20 who are researchers. 21 MS. WARNER: Hi, I'm Ellen Warner from the 22 National Heart, Lung and Blood Institute and I 313 1 would like to suggest that early in August, you 2 look at the NIH training web site, we are going to 3 be releasing two new program announcements. One is 4 a T-15 institutional training grant in bioethics, 5 the other is a KO1 mentored scientist research 6 award in bioethics training. And I think they 7 would be of great interest to you all. 8 CHAIRPERSON MARSHALL: Thank you very 9 much. 10 Mary Kay is on the agenda next. We have 11 an update and a discussion from a working group 12 that is a relatively new working group. It as 13 formed at our last meeting. Mary Kay is the 14 chairperson, Mary Kay Pelias. If you want to give 15 us an update. And I know that this discussion is 16 actually going to sort of segue into tomorrow's 17 work as well. 18 DR. PELIAS: Thank you, Mary Faith. As 19 the members of the Committee know, we were 20 constituted at our last meeting and it started out 21 with discussion of perhaps we were going to go 22 directly into questions of genetics. And then we 314 1 sort of backtracked and said, well, maybe before we 2 do genetics, perhaps we ought to get into the issue 3 of human subjects and discuss whether or not the 4 definition in the federal regs, the definition of 5 human subjects is appropriate and then maybe we 6 would take this discussion down to the issue of 7 third parties. And someday perhaps in the future 8 we'll get on to the issue of genetics. 9 Today I would like to give you a rundown 10 of what we've been up to for the last couple of 11 months and I would invite you to follow along in 12 the materials that you have because some of it I'm 13 going to skip over rather quickly. And then I'll 14 give you a little bit more details about questions 15 that have come up for our workgroup. 16 Whenever I get into a discussion like 17 this, I always believe that it's important to look 18 for a little while at the historical perspective 19 because I don't believe that we can go forward 20 without knowing where we have come from. So part 21 of our attention for the last couple of months has 22 been devoted to the historical perspective 315 1 beginning with the Nuremberg Code and some of the 2 language that we draw from the Nuremberg Code about 3 human subjects including language and phrases that 4 go to voluntary consent and legal capacity, 5 knowledge, comprehension, free power of choice and 6 without constraint or coercion. These are very 7 important phrases. And I think with respect to 8 the Nuremberg Code they address the interests of 9 the individual subject. 10 Quite a while after the Nuremberg Code was 11 promulgated in 1946, we had the advent of the 12 Declaration of Helsinki and I would summarize that 13 very quickly by saying that first of all it 14 stresses international questions, but also I 15 believe that it's written from the perspective of 16 the investigators, the researchers, the 17 professionals. It calls on investigators and so- 18 called clinically competent medical persons to 19 conduct themselves in ways that are appropriate 20 protections for the people that participate as 21 subjects in human research. So we have from the 22 Declaration of Helsinki language like "freely given 316 1 informed consent"; "dependant relationship"; 2 "protector of the life and health of the subject"; 3 and ideas about discontinuing things if they seem 4 to become harmful. 5 We heard this morning from Dr. Wood more 6 information about experimentation with human 7 subjects that went on into the 1970s including 8 mention of Tuskeegee and Willowbrook. In addition 9 to those two travesties, we also have history in 10 Jewish Chronic Disease Hospital about whether or 11 not cancer is infectious. And we have a very long 12 history of radiation exposure both in civilian and 13 military arenas. 14 We move on up a little bit further and we 15 have the Belmont Report and then eventually the 16 regulations that bring us all here together today. 17 Specifically we have the establishment of our 18 Institutional Review Boards, and that famous 19 Subpart A of 45 CFR 46. I should not have 20 included, by the way, in my write-up the topics of 21 Subparts B, C, and D, as part of the common rule, 22 but that was my error when I was writing this up 317 1 very quickly. 2 With regard to what we've been up to for 3 the last couple of months, we met briefly at the 4 end of our last meeting here in Washington. A 5 short time after that I circulated a document 6 called, "Defining Human Subjects" which included 7 the current definition in the Federal Regulations 8 as well as the historical perspective and questions 9 about language in the current definition. I also 10 submitted a new and extremely unrefined definition, 11 almost intentionally to try to generate some 12 discussion and that certainly worked. And we 13 considered possible pathways for further 14 deliberation. 15 We had a conference call, then we put 16 together all the information from the conference 17 call and send out a second document and had yet 18 another conference call. And we came at the end of 19 the second discussion on the telephone, we came to 20 a few conclusions that I can share with you now. 21 I had considered the possibility of 22 reading into this record the current definition of 318 1 a human subject because we spent a lot of time 2 talking about the language. But I think I will not 3 do that. I will rather skip on down to a critique 4 of the current definition beginning with questions 5 of language. We went over and over phrases. We 6 agreed that the parentheticals, three of them 7 anyway, the first three in the current definition 8 are really not necessary. We agreed, for example, 9 that the definition of "investigator" would be 10 perhaps better if it said that an investigator is 11 any person who conducts a research investigation or 12 who participates as a member of a research 13 investigation team. 14 The most troublesome part of our 15 deliberations over the last couple of months 16 continues to be what constitutes private 17 information? Some of our members suggest that 18 private information should be defined according to 19 the kind of information that is collected. Is it 20 sensitive? Is it potentially harmful? Is it 21 embarrassing if it's improperly disclosed? 22 The next question is, can we really define 319 1 any of those words, sensitive, or potentially 2 harmful or embarrassing, and if so, from whose 3 point of view? 4 There was some discussion about whether we 5 should distinguish between collecting personal 6 information about people and how personal 7 information might be distinguished from private 8 information. And is it private information if it 9 can't be linked to an identifiable individual? 10 There are a number of other questions 11 about whether or not, for example, we can define 12 private information as privileged and confidential; 13 is private information the kind of information we 14 can collect from a subject or does it necessarily 15 include information that is gathered from a subject 16 about a third party? These are all questions that 17 we are wrestling with right now. 18 One member of our working group went back 19 to the question of what is research and noted that 20 the definition of research is the systematic 21 collection of data with the intent of advancing 22 scientific knowledge. And it was this observation 320 1 that brought us into the problem of defining 2 parties. 3 We've heard a lot about parties, first 4 parties, second parties and third parties, and for 5 the sake of clarity and conciseness right now, we 6 can say that first parties are investigators, 7 second parties are those subjects that have direct 8 contact with the investigator, they may also 9 include those who are studied directly by the 10 investigator either through direct intervention or 11 use of pre-existing data or tissue. 12 And third parties which are generating so 13 much trouble now are perhaps persons about whom the 14 investigator gathers information from second 15 parties. Now, we haven't come to conclusions about 16 this yet, but this sort of outlines the directions 17 that we are headed. 18 There was considerable discussion in our 19 group about the question of changing or amending 20 federal regulations and my feeling at the end of 21 our second conference call was that people threw up 22 their hands and said, we can't change the federal 321 1 regulations, they're essentially written in stone. 2 We have an acute problem here that we have to 3 address and perhaps the way to address this is to 4 formulate guidelines within the current federal 5 regulations to give IRBs some sort of a handle on 6 how to deal with this difficult question of third 7 parties. 8 So we went on then to this idea of 9 crafting guidelines that would help IRBs number 10 one, identify human subjects and third parties in 11 biomedical research. And number two, questions of 12 considering waivers for informed consent from the 13 third parties. 14 We had a long discussion of our ideas 15 about how we would include certain individuals in 16 the category of human subjects. And I think 17 without reading all of these various comments I 18 think I've generally summarized that already. 19 Human subjects will be those individuals with whom 20 an investigator has direct contact and third 21 parties will continue, at least for the time being 22 to be those individuals that do not have direct 322 1 contact with the investigator, but about whom the 2 investigator gets information from the research 3 subjects, the real persons that are in contact with 4 each other. 5 We also would consider standards for 6 handling private information and this is going to 7 continue to be a very difficult area for us. Some 8 of the comments that came in to us came in from the 9 various members of the working group were these: 10 private sensitive, identifiable information whether 11 about a research subject or a third party must be 12 protected. Investigators should secure data at all 13 stages of research. When data identifying research 14 participants are no longer necessary to the 15 progress of the research investigators should take 16 steps to deidentify research records. 17 So we've got a lot of ideas just in this 18 one opinion from one member of our group. But I 19 will say that the feeling I have over all the 20 comments of the members of our group is this. We 21 feel very, very strongly that any data that are 22 collected or any information that is collected in 323 1 the context of a research project should be very, 2 very carefully protected and guarded. How we are 3 going to do this, I don't know. We talk about 4 stiff fines and sanctions according to the HIPAA 5 regulations, or whatever, but I think the consensus 6 of our group at this time is that we must establish 7 safeguards for this information and make violations 8 of the safeguards subject to severe strong 9 sanctions. 10 So we have a few other questions to get 11 into, we need a working definition, for example, of 12 identifiable information with regard to the 13 language of the current definition of human 14 subjects. We really don't quite know what it means 15 to make information public, we need a definition 16 there. We need to certainly formulate our 17 guidelines for our IRBs, so that IRBs will have a 18 handle on how to approach individual investigators 19 and how to judge research proposals so that any 20 information that is collected will be very, very 21 carefully guarded. 22 I think this pretty much summarizes what 324 1 we've been up to. We are concerned about who the 2 research subjects are and defining third parties. 3 We are very concerned safeguarding information, and 4 we have a couple of other issues that are going to 5 enter into these discussions as we continue. 6 First of all, does a third party become a 7 research subject as soon as an investigator obtains 8 identifiable information about him or her? This 9 raises a question of what do we mean by 10 identifiable? Sometimes, for example, we might be 11 collecting a family history and have a full name 12 and birth date, but we have no idea how to get in 13 touch with that individual. 14 On the other hand, we might have 15 information about an individual that would let us 16 find this person, this third party, and contact 17 this thirds party. But then we raise the question 18 of, if we contact a third party without an 19 introduction by the person who talked about this 20 person to begin with, are we going to be invading 21 that individual's privacy. So we've got a real, 22 real problem here. 325 1 And another question that was raised, this 2 is the last one that we will have to deal with, the 3 last question that we raised is, what kind of 4 information are we going to be collecting about our 5 subjects and our third parties? Whether we should 6 collect data and ask questions that are only 7 immediately relevant to the study that we're doing, 8 or whether or not we're going to deal with the 9 question of very broad questionnaires that are sent 10 out to people and all sorts of information that is 11 collected that doesn't necessarily have direct 12 relevance to a particular study. A few members of 13 our group have suggested that we should try to 14 avoid expansive and far-reaching questionnaires and 15 that we should limit what we are allowing -- the 16 kind of information that we are allowing people to 17 collect to information that is reasonably relevant 18 to the study that we're doing. 19 So that's where we are at this stage of 20 the game. I understand that we're going to have 21 considerably more discussion after this with the 22 two working groups meeting together right after 326 1 this assembly. And we'll more public discussion of 2 these issues tomorrow evening. So that explains 3 why we're running a little late, but that's it for 4 right now. 5 CHAIRPERSON MARSHALL: Mary Kay, thank you 6 very much. I'm reading Mark Barnes' mind and he's 7 saying, thank God I'm not chairing that working 8 group. 9 [Laughter.] 10 CHAIRPERSON MARSHALL: You all have taken 11 on some very difficult, core conceptual work. And 12 it sounds as though you're making beautiful 13 progress. And I an tell you, having served on a 14 recent 407 panel and trying to parse out the 15 meaning of the word "serious" just how difficult 16 this very basic work is. So, I commend you and 17 your fellow working group members. 18 Let me open the floor up to other 19 committee members, but the framework that you've 20 provided and the steps that you've taken in this 21 direction look wonderful. So thank you very much. 22 Elliot. 327 1 DR. DORFF: First of all I want to echo 2 that. I mean, what you're talking about is 3 absolutely critical and very messy. Okay. And so 4 -- I mean, so if there are difficulties along these 5 lines, both in the articulation of what the issues 6 are and what to do about them, that's to be 7 expected and whatever headway you can make is 8 applauded. And my comments here are in that 9 spirit. Right. I'm just going to try to tell you 10 how we reacted to some of the things that were in 11 this. 12 First of all, matters of language. The 13 first thing that you raise is the issue of living. 14 A human subject means a living individual about 15 whom an investigator or professional student 16 conducting research obtains one or two, right? And 17 somebody raised the question of living. Well, of 18 course, that then, you know, in the bioethical 19 literature raises the whole issue of when does life 20 begin. Right. You know, the old -- you know, the 21 Catholics think it's when sperm and egg come 22 together. There are those who think that it's when 328 1 quickening happens, the Supreme Court said, that 2 when the fetus was viable, there are those who 3 think that when it -- you know, the fetus is born. 4 And then Jews think it's when your child gets into 5 medical school. 6 [Laughter.] 7 DR. DORFF: But the point -- I'm sorry, I 8 couldn't resist. 9 AUDIENCE PARTICIPANT: [Off mic.] 10 [Laughter.] 11 DR. DORFF: That's right. But anyway, the 12 point that I'm after here is that when we're 13 talking about a living individual, one of -- you 14 should be aware of the fact that there are some 15 critical philosophical and also frankly political 16 issues involved in what's the status of the fetus. 17 For that matter, at this moment, what's the status 18 of a sperm and an egg in a petri dish? You know, 19 is that in terms of the debate about stem cell 20 research, I mean, all of that is really critical 21 stuff which I would suggest that you try to punt 22 on. Okay. 329 1 What I mean by that is, if you were to 2 talk about saying a human subject is a person, 3 about whom an investigator and just leave the word 4 "person" there to basically avoid everything that 5 happens in regard to what goes on in utero unless 6 you want to apply all of this to that. And what we 7 were just hearing before the break is that where 8 there were definitions of "fetus" and what could 9 happen with the fetus, I mean, you may want to 10 include that in your definition as something that's 11 going to be -- you know, to which you are going to 12 be applying these regulations. But you should at 13 least be aware of that issue. 14 And on the other end of things, I think 15 that research on dead people is a very different 16 sort, but even the dead require a certain amount of 17 respect on our part. And so you may want -- you 18 know, there may be -- I mean, I think the 19 regulations would be far less stringent, but 20 nevertheless you want to have at least something to 21 say about the sacredness of the human body even in 22 death. 330 1 The second thing is, investigator. I'm on 2 page 3. "Investigator" would be better defined as 3 any person who conducts a research investigation or 4 participates as a member of a research 5 investigation team. The immediate problem with 6 that is you cannot use the word that you're 7 defining in the definition. So what I would do is 8 just simply cut out "investigation" -- both uses of 9 "investigation" in the definition and then you're 10 all right. Investigator would be better defined as 11 any person who conducts research or who 12 participates as a member of a research team. 13 Then, the third thing is, what is 14 "research"? I'm on page 4. The current definition 15 of "research" is the systematic collection of data 16 with the intent of advancing scientific knowledge. 17 I think that's fine, but I wanted you the be aware 18 of the fact that part of the real problems in human 19 subject protection, I'm thinking about the Nazi 20 experiments, for example, had to do with 21 manipulating data, manipulating circumstances in 22 order to be able to create the data as to what 331 1 would happen when you froze bodies, for example. 2 Right. So, if you understand the systematic 3 collection of data very broadly to mean not just 4 simply collecting what is there, but also 5 manipulating what's there to find out certain facts 6 about what happens to people when something happens 7 to them, then that's fine. I mean, the definition 8 can stand. But I think you need to understand it 9 broadly. 10 The fourth one that I wanted to make was 11 that on page 5, where you go through guidelines for 12 inclusion as a human subject, the part that was not 13 clear to me throughout all of that is what is the 14 purpose of the definition of sometimes it seems to 15 be b for consent requirements. In other words, 16 when do we have a human subject such as you need 17 consent in order to be able to do the research 18 morally? And sometimes that had to do with privacy 19 issues. And it may not be -- those two things may 20 not be the same. 21 In other words, what is a human subject -- 22 when we were talking this morning, where are the 332 1 children, for example, right? Children are 2 certainly human subjects, but they may not be able 3 to give consent. At the moment they give assent. 4 And we're talking about teenagers and whether they 5 can give consent. So, I mean, I think you need to 6 be -- in that section, Section V. You need to be 7 very clear as to what the purpose is that you have 8 in mind and then ask the question about what seems 9 reasonable when you're trying to figure out what 10 the rules should be in regard to consent, and what 11 the rules should be in regard to privacy. But 12 understand that those are the two issues at least 13 that you've identified here that you are after and 14 you should think about in terms of those things. 15 And the last thing that I wanted to say 16 was on page 6 where you're talking about privacy. 17 It reminded me frankly of a discussion in the 18 Talmud in regard to embarrassment. When according 19 to the Talmud, when I -- if I strike you, if I 20 assault you, then I am responsible for five 21 different types of damages. And one of them is for 22 the embarrassment that I caused you. So then the 333 1 Talmud then asks, well, how do you define 2 "embarrassment"? Is it that the victim had to 3 actually fee the embarrassment and be aware of it, 4 or what would happen if I insulted you when you 5 were sleeping and so you weren't even aware of it? 6 Is that still embarrassment? And what would happen 7 even if I was awake and I wasn't embarrassed myself 8 but everybody else knew that I had just been 9 dissed? And that's a technical term. 10 [Laughter.] 11 DR. DORFF: Now, the thing is, I think 12 that's a similar kind of discussion here in terms 13 of what is private. One way to go with it is that 14 what is private is whatever I want -- whatever 15 information I want to retain about myself so that 16 nobody else knows about, in which case the 17 definition is dependent upon the individual. 18 Another way to go with it is that it 19 depends upon the community, what the community as a 20 whole thinks ought to be private, whether the 21 person thinks so or not. The person may have -- 22 may choose to divulge those things, if that person 334 1 wants to, but that the community retains as private 2 certain types of information which get defined as 3 being inherently private; right. 4 A third way to go to it has to do with 5 results. In other words, that is private which 6 could be damaging to a person if it were known, and 7 that which is not private, if it's not going to be 8 damaging -- first you have to ask what "damaging" 9 means, but the point is that those are at least 10 three different ways of attacking the problem of 11 what constitutes private. 12 CHAIRPERSON MARSHALL: I have Susan, then 13 Bob, then Abbey. 14 DR. KORNETSKY: Mary Kay, I think you did 15 a wonderful job outlining the issues. And I'm not 16 on the working group, but sort of trying to read 17 through sort of end results, I think there's one 18 particular area that isn't on your list and I'm 19 just bringing it up. I think regardless of whether 20 you consider a third party a human subject or not, 21 you're going to probably boil down to the issue of 22 informed consent. Regardless of what you call 335 1 them, when you need to think about obtaining that 2 or not. And if you look to the common rule about 3 informed consent and waivers of informed consent, 4 and I think about this on a daily basis with human 5 subjects, one of the things that probably you will 6 need to think about is one of the categories if you 7 want to waive it is that it is impracticable to get 8 informed consent. And I think from having spent 9 probably two or three months thinking about that 10 and trying to give our investigators guidance, I 11 don't see a way that you're going to be able to 12 avoid that in the situation. 13 CHAIRPERSON MARSHALL: Bob. 14 DR. R. LEVINE: I want to second the 15 congratulations to the working group and to Mary 16 Kay. I'm very glad you began with the discussion 17 of the relevant histories. I want to just add a 18 couple of points to that. 19 The first is that the National Commission 20 which gave the recommendations that formed the 21 framework for the current regulatory system never 22 defined human subject. The reason the regulation 336 1 writers felt it necessary to define the human 2 subject is that they wanted to extend the reach of 3 the regulatory standards to medical records review 4 which many people were arguing did not entail 5 interaction with the person, but you were getting 6 information about living persons. No one ever 7 imagined that it would be applied to the walking 8 around relatives of people that you were actually 9 interviewing. And that definition stood there 10 without having been interpreted as applying to 11 living relatives until the Virginia Commonwealth 12 case about, what, one or two years ago. 13 In the current regulations we find a lot 14 of the requirements for informed consent are 15 compared with what goes on in medical practice. It 16 says, for example, that you don't have to get 17 written documentation of consent if the procedure 18 you are doing for research purposes is one that is 19 ordinarily not -- consent to do this procedure is 20 ordinarily not documented in a written form in the 21 practice of medicine. 22 This brings me into considering analogies 337 1 with medicine. In medicine a routine medical 2 history involves asking whoever the identified 3 patient is all sorts of questions about their 4 personal history and their relatives' history. It 5 goes into greater detail than almost any 6 interviewer survey instrument that would be 7 employed by a geneticist or by a sociologist or by 8 a psychologist. 9 To be consistent, we would have to say 10 that before a doctor could get a family history 11 that the doctor would have to get permission from 12 all of the patient's relatives to get this. That's 13 what Susan just reminded us, that it would violate 14 the impracticability standard. 15 The other thing is that in research the 16 confidentiality safeguards are very, very much more 17 secure than they are in medical practice. I had a 18 patient who was a medical records librarian who 19 refused to talk to me as long as I had a pen in my 20 hand. But now what happens routinely when you go 21 into the hospital, you waive your rights to 22 privacy. You sign a document saying that the 338 1 hospital has the authority to turn your entire 2 medical record over to your insurance company. It 3 doesn't say just that part that has to do with 4 determining what should be billed in this 5 admission, but everything in your medical record 6 which is a very much plenary violation of privacy 7 standards than anything that goes on in the 8 research context. 9 The other thing is, what about the problem 10 about people like the father at Virginia 11 Commonwealth who was offended because they asked 12 his daughter to comment on his genitals. I think 13 the way we usually protect ourselves against such 14 disclosures is that we don't tell our children such 15 things. They shouldn't know it in the first place. 16 But if it comes up in the course of conducting 17 social or genetic research, the odds that it will 18 be further disclosed are very much less in a social 19 science or genetics context than they would be in 20 medical practice. 21 All of this is just various little points 22 that I would use to support my argument that in 339 1 almost all research of the type we're talking 2 about, the only person who should be called upon to 3 consent is the person they're actually talking to 4 with the exception of when you're talking to little 5 children. That's why we have limitations of the 6 exemptions from the federal regulations. They say 7 these apply to everything except when you're 8 talking to children. And that's because we don't 9 think children age six, seven, eight, ten know 10 enough about what the family would like to keep 11 private to be proper guardians of this information. 12 So we then say, well, at least they have to submit 13 their plan to an IRB not exempt from coverage by 14 the regulations. 15 CHAIRPERSON MARSHALL: Thank you, Bob. I 16 have Abbey and then Bob. 17 MS. MEYERS: Well, one of the issues here 18 is that when we look at this third-party question, 19 which is a new question, I don't think it's been 20 really raised before, before the Virginia twin 21 study took place, that we can't change the laws, 22 and we can't change the regulations. But even if 340 1 we could, we're advisory to the HHS Secretary and 2 research isn't just part of HHS. So if we said 3 that the law has to be changed or the regulations 4 have to be changed, the interpretation of human 5 subject in the common rule has to be changed, it 6 would take 100 years and have to go through what, 7 17 federal agencies; right? 8 Do you want to answer that? 9 DR. KOSKI: Yeah, if I could just address 10 it. We frequently hear that kind of talk thrown 11 around. I think it's time to stop that. I think 12 that in fact where there is thoughtful change 13 required in regulations that you would find all of 14 the federal agencies that subscribe to the common 15 rule stepping up to the plate to engage in that. 16 In fact most of them are represented here. And I 17 don't think that continuing -- and I'm not picking 18 on you with this, Abbey, I'm just getting it out 19 there for everybody else, I just don't think that 20 continuing that sort of mythology is serving our 21 interests. 22 I think it's time to say that where we 341 1 need to change, we should look at it and we should 2 change it and we can do that. So, you know, but 3 again, the emphasis has to be on thoughtful 4 delivery things that will serve the purposes of 5 responsibly conducting research. But let's get 6 that off the table now. 7 MS. MEYERS: The most we could do is 8 recommend that they be changed. Right? Because 9 we're advisory to the HHS Secretary. 10 Okay. So the issues then in the Virginia 11 twins study was that -- from my perspective anyway, 12 the questions that were asked were not relevant at 13 all to this young girl being a twin, you know, 14 whether her father had deformed organs or whatever 15 had absolutely nothing to do with it. 16 So I think that the definition that we're 17 talking about the research has to be relevant to 18 the questions is really important. But the 19 primary thing is, no matter what, whether you're 20 talking about your dead grandmother or, you know, 21 your uncle who never threw anything away and they 22 needed a backhoe to clean out his house because he 342 1 was an obsessive/compulsive, or whatever, those 2 kinds of things need to be private without even 3 guessing whether it would be embarrassing to him or 4 not. I think that the primary aim here is a 5 guarantee on confidentiality for -- and not 6 identifying a human being with the data. 7 And if we could just de-identify the data, 8 then you could collect all the information you want 9 without having to worry about stepping on anybody's 10 rights whether they're dead or alive. I think that 11 it's wrong to expect somebody to get a waiver for a 12 relative who they may not have talked to for 20 13 years, but we need the information for research 14 purposes and there's no way to tell a person you 15 shouldn't be talking about your uncle that way 16 because your uncle has rights and you have to be 17 confidential. I think the information is okay. It 18 has to be collected, but it has to be de- 19 identified, that's the main thing. 20 DR. PELIAS: I have one more comment about 21 language and that's the word "de-identify"; it 22 seems to me that it sound awfully close to 343 1 "anonymize" and the question there is who has the 2 right to make those decisions to take identifiers 3 off of data. We'll have to deal with that sometime 4 down the line. But that's just another question to 5 throw into the hopper at this time. 6 CHAIRPERSON MARSHALL: I'm just going to 7 make a procedural remark here and that is that we 8 are actually running overtime and we do have two 9 working groups that are going to continue to work 10 after the meeting. So I am going to close the 11 questioning at 5:00 knowing that we will have time 12 tomorrow to revisit the issue that's on the table. 13 So if your question or your remarks aren't made 14 this afternoon, there will be time for them 15 tomorrow. 16 I have Bob and Adil, Mark and Judy as the 17 order depending on how the time goes. 18 DR. RICH: I would like to just continue 19 the question of de-identification for just a moment 20 with the concern that is in at least one of the 21 points here that a research project can be 22 identified as a discrete entity and then at the 344 1 conclusion of the project, the data are de- 2 identified. 3 And as you know better than anyone here as 4 a geneticist, Mary Faith, I think increasingly as 5 we move into areas where data are in the form of 6 archived tissues, where the questions haven't been 7 considered yet, that we may be needing those 8 tissues for research purposes a decade from now, 9 the issue of de-identification becomes very 10 problematic. And that's not to say that I disagree 11 at all with the idea that there needs to be a sharp 12 separation between individuals who have access to 13 the medical records and who could re-identify them 14 and the investigators who don't need a specific 15 identifier identifiable information. But I think 16 there are very problematic issues if we are to 17 actually be able to exploit the incredible power 18 that we will be gaining by these archived tissues 19 and archived data samples that we need to somehow 20 be able to get back and ask the questions ten years 21 from now that we don't even understand about right 22 now. 345 1 CHAIRPERSON MARSHALL: Adil. 2 DR. SHAMOO: I think this working group 3 brings the general question which I have brought to 4 your attention through e-mails and every meeting 5 and Bob Levine was kind enough to bring that up all 6 over again and that is the general issue. What 7 human research protection, what are we covering? 8 There is research done with human subjects which is 9 not covered now as we all know. Definition of 10 issue, minimal risk, direct medical benefits. The 11 whole definition of what research -- these are the 12 kind of general issues and back final reports have 13 at -- the global issue. And we're really, we're 14 sort of again and again avoiding the amount. I 15 plead with Mary Faith and Dr. Koski, maybe we 16 should address them at the next meeting as an 17 agenda item because they are going to come up all 18 the time. And then doing them within each work 19 group may not serve the overall purpose. That's 20 one comment. 21 And then I have a point of information 22 from Kate. I did ask what portion of proceedings, 346 1 work groups, e-mails, become an official part of 2 the record of this committee for the public to see 3 in the web site or other documents. Thank you. 4 MS. GOTTFRIED: Wait and just in a quick 5 response. I definitely have looked into that. 6 Unfortunately the people who were here earlier 7 today are the FACA -- some FACA experts who would 8 have been able to opine for you specifically on 9 that. But in light of that I will get their 10 official response and distribute it to the 11 committee. 12 CHAIRPERSON MARSHALL: And, Adil, actually 13 I wanted to thank you. You and I have talked about 14 this general issue and the fact that in light of 15 our different workgroups we may be looking at the 16 trees, but not necessarily the forest. And I think 17 that tomorrow beginning with Congresswoman DeGette 18 we're going to be taking -- we're going to be 19 looking at taking that broad overview. And 20 certainly the folks from the NBAC and so forth. So 21 I think that the whole point of tomorrow morning's 22 session is for us as a committee to begin to get a 347 1 sense of the landscape to help us start to form a 2 larger picture in our own mind collectively as a 3 committee of where we want to go and how we want to 4 frame issues that aren't necessarily being 5 addressed more concretely or in a more narrow 6 fashion. 7 So I would hope that the session beginning 8 with our first speaker tomorrow morning will head 9 us in that direction and that we may also wind up 10 the end of the day with some plans for moving 11 forward in those directions. 12 And I'll take one more question. Mark. 13 MR. BARNES: A general comment, perhaps to 14 set the stage for the fact that we're going to hear 15 from Julie Kaneshiro tomorrow about the 16 relationship between HIPAA and clinical research. 17 I just wanted to point out the following 18 in terms of the workgroup, the charge of the third- 19 party workgroup here. We do have these new federal 20 regulations that goes to what Bob Levine was 21 talking about too. We did these new federal 22 regulations that govern medical privacy and 348 1 confidentiality that essentially have done the 2 following. They basically have, one could say, for 3 the research process, they have unbundled the 4 privacy rights, the right to the use and disclosure 5 of one's medical information. They have unbundled 6 that from the informed consent process, although 7 one could say it's still part of the informed 8 consent process. And there are a separate set of 9 rights and obligations that adhere to an 10 institutions or a researcher's use and disclosure 11 of medical information. 12 One thing that we are talking about the in 13 the third-party work group is in fact the 14 definition of who is a research subject and at what 15 point does the collection of data cross the line -- 16 become so intrusive or so comprehensive that it 17 really crosses the line and another person who has 18 not had contact with the research subject does 19 become the subject of research. But there's 20 another thing that the third-party workgroup really 21 needs to grapple with too which is that under HIPAA 22 that person -- information that is collected about 349 1 that third party may become at some point, 2 depending on HHS's interpretation of the HIPAA 3 regulations, that person, that third party, that 4 may become protected help information of that third 5 party in which case the third party may not need to 6 consent to the research for informed consent 7 purposes, but may need to consent for the 8 additional uses and disclosures of the information. 9 That isn't -- it's an unintended 10 consequence of the way in which the HIPAA regs were 11 -- and perhaps statue, but really more the regs 12 were written. But the point is that the HHS 13 Secretary who is the one who ultimately has 14 authority over -- or at least part of the authority 15 over the common rule is also the one whose general 16 counsel is writing interpretations every day of the 17 HIPAA regulations. So one of the things that we 18 need to be cognizant of, I think in the third-party 19 workgroup, is not simply that we're coming on 20 informed consent standards, but also that we are 21 advising the -- through Greg, through Dr. Koski and 22 his staff -- the Secretary of HHS about what ought 350 1 to be the permissible uses and disclosures and when 2 or under what circumstances the HIPAA regulations 3 ought to be read to require or not to require the 4 gaining of that consent or authorization under 5 HIPAA for the additional uses and disclosures. 6 CHAIRPERSON MARSHALL: Let us end here. I 7 would like to thank the Committee as a whole for 8 all of your hard work prior to today's meeting, 9 those of you who are on working groups. Some of 10 the folks out in the audience have participated in 11 the working groups and thank you for being here. 12 Mark and Alan, thank you for your 13 wonderful work. We have come to some closure today 14 on some of our very early projects and I think it 15 felt good. The process felt good. We arrived at 16 consensus. We are moving forward well. And I look 17 forward to an excellent meeting tomorrow. 18 I want to thank Kate for all of her hard 19 work in pulling this meeting together. I want to 20 thank Greg for his continued support and most 21 excellent advice. Those of you on the committee 22 who might want to discuss food could -- we've taken 351 1 care of food. Okay. 2 The two workgroups will meet then here in 3 this room in just a few moment. So -- yes? 4 AUDIENCE PARTICIPANT: [Off mic.] 5 CHAIRPERSON MARSHALL: Kate is going to 6 pass that information out to all. 7 DR. F. LEVINE: Can I just say, I think 8 it's less clear to the social and behavioral 9 science working group that since the social and 10 behavioral science working group is also addressing 11 the issue of third parties that those of us who are 12 present or have become present will join the third 13 party working group after the conclusion of this to 14 continue that conversation. But not everyone in 15 the room knew that. Some people are looking 16 around. Who is coming where? 17 CHAIRPERSON MARSHALL: Thank you very 18 much, Felice, for clarifying that. So thank you 19 all very much for a very successful day and we'll 20 see you tomorrow. 21 [Whereupon, at 5:00 p.m., the meeting was 22 recessed to be reconvened on Tuesday, July 31, 352 1 2001, at 8:30 a.m.] 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 353 1 CERTIFICATE OF OFFICIAL REPORTER 2 This is to certify that the attached 3 proceedings before the National Human Research 4 Protections Advisory Committee held Monday, July 5 30, 2001, was held as herein appears, and that this 6 is the original verbatim transcript thereof, and is 7 a full correct transcription of the proceedings. 8 9 10 11 12 Gerald T. Brooks, Sr. 13 Official Reporter 14 15 16 17 18 19 20 21 22