1 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTIONS + + + + + MEETING + + + + + Tuesday, August 2, 2005 + + + + + The Advisory Committee met in the Jefferson Ballroom in the Radisson Hotel Old Town Alexandria, 901 North Fairfax Street, Alexandria, Virginia, at 8:30 a.m., ERNEST PRENTICE, Ph.D., Chairman, presiding. PRESENT: ERNEST D. PRENTICE, Ph.D., Chairman BERNARD A. SCHWETZ, D.V.M., Ph.D., Executive Secretary CATHERINE SLATINSHEK, M.A., Executive Director THOMAS L. ADAMS, CAE, Member MARK BARNES, J.D., LL.M., Co-Chair CELIA B. FISHER, Ph.D., Member NANCY L. JONES, Ph.D., Member FELIX A. KHIN-MUANG-GYI, Pharm. D., Member SUSAN KORNETSKY, M.P.H., Member ADA SUE SELWITZ, M.A., Member SUSAN L. WEINER, Ph.D., Member 2 Ex Officio Members: PEG BARRATT, Ph.D., National Science Foundation HOWARD L. BRADLEY, Social Security Administration KATHRYN LYNN CATES, M.D., U.S. Department of Veterans Affairs FRANCIS CHESLEY, Agency for Healthcare Research and Quality ROGER CORTESI, U.S. Environmental Protection Agency PATTY DECOT, U.S. Department of Defense DAVID LePAY, M.D., Ph.D., Food and Drug Administration AMY PATTERSON, National Institutes of Health LAWRENCE UHTEG, NIST ALSO PRESENT: KELLEY BOOHER, Office of Human Research Protections MICHAEL CAROME, Office of Human Research Protections JULIE KANESHIRO, Office of Human Research Protections IVOR PRITCHARD, Office of Human Research Protections KEVIN PROHASKA, Office of Human Research Protections IRENE STITH-COLEMAN, Office of Human Research Protections 3 I-N-D-E-X AGENDA ITEM PAGE Welcome: Opening Remarks 4 Ernest Prentice, Ph.D. Chairman, SACHRP Panel #1 -- Perspectives of research subjects, 7 representatives and advocates Carolina Hinestrosa, Executive Vice 48 President for Programs and Planning, National Breast Cancer Coalition Paul Gelsinger, Citizens for Responsible 7 Care and Research (CIRCARE) Bob Huff, Editor, Gay Men's Health 26 Treatment Issues, Gay Men's Health Crisis, New York Panel #2 -- Perspectives research subjects, 112 representatives and advocates (con't) Wanda Jones, Director, Office of Women's 112 Health, Office of Public Health and Science, Department of Health and Human Services Linda Wachtel, Children's Brain Tumor 130 Foundation Ron Honberg, National Director for Policy 148 and Legal Affairs, National Alliance of the Mentally Ill (NAMI) Panel #3 -- Perspectives of research subjects, 190 representatives and advocates (con't) Jeffrey Henderson, MD, Black Hills Center 227 for American Indian Health Dr. Cora B. Marrett, Senior Vice 190 President, University of Wisconsin Darrell Forney, M.D., Johns Hopkins 207 University Public Comment 298 Follow-up discussions/wrap-up/adjourn 305 4 1 P-R-O-C-E-E-D-I-N-G-S 2 (8:33 a.m.) 3 WELCOME: OPENING REMARKS 4 CHAIRMAN PRENTICE: Good morning, 5 everybody. We have got a tight agenda today. So I 6 would like to get started. As is customary, I am 7 going to provide a brief overview of our agenda today. 8 The entire day is devoted to perspectives 9 of research subjects, representatives, and advocates. 10 And this slide gives you the agenda for the morning. 11 Panel 1 will have three individuals: Carolina 12 Hinestrosa, Paul Gelsinger, and Bob Huff. Then at 13 10:30, we're going to take a break. 14 Panel number 2, we will also have three 15 individuals: Wanda Jones, Linda Wachtel, and Ron 16 Honberg. At 12:00 o'clock, we'll have a lunch break. 17 We'll reconvene at 1:00 o'clock, where we 18 again have three more panelists: Jeffrey Henderson, 19 Cora Marrett, and Darrell Forney. We're going to have 20 another public comment period between 3:00 and 3:30, 21 3:30 to 4:30 follow-up discussions and our wrap-up. 22 And then we'll adjourn I'm sure no later than 4:30. 5 1 I think this is a very, very important day 2 for us because while we have been meeting for about 3 the last two years, this is the first time we have 4 actually devoted an entire day to public perspectives. 5 So we're really looking forward to hearing from the 6 individuals who have been invited. And we would like 7 to thank them for taking their time to come and talk 8 to us. 9 I think you're going to find it's going to 10 be a very interactive session with all of the 11 individuals. I would remind the panelists that there 12 are time frames we need to adhere to. We're talking, 13 really, about 15-18 minutes of presentation time, 14 which will allow adequate time for discussion. 15 Now, the format for the panels is that we 16 ask each individual to come up in their turn. And 17 then they are perfectly free to sit down here at the 18 head table if they like, rather than having all three 19 panelists sit at the head table right from the 20 beginning, or if you prefer, you can all come up. It 21 really doesn't matter, but normally that's the way we 22 do it. 6 1 Now, is Carolina Hinestrosa here yet? 2 Okay. Well, we're going to take the panelists a 3 little bit out of order. Paul, would you be prepared 4 to go first, instead of second? I would appreciate 5 that. 6 I'm going to introduce all of the 7 panelists simultaneously. And I'm going to do that 8 from over there. Okay. I would like to introduce 9 Paul Gelsinger first. 10 And I won't read Paul's entire bio. Paul 11 is well-known to all of us in the IRB and research 12 community because of the tragic death of his son in 13 September of 1999 in a gene therapy experiment. 14 Since then he has become an advocate for 15 reform in the system. And he spoke at many, many 16 conferences, testified before the Senate, and has also 17 gone overseas, as a matter of fact, to talk to groups 18 over there. So, Paul, we really appreciate you taking 19 your time. And we're looking forward to your 20 comments. 21 MR. GELSINGER: Thank you, Ernie. And 22 thank you, SACHRP, for inviting me here, Ernie. 7 1 PANEL 1: PERSPECTIVES OF RESEARCH SUBJECTS, 2 REPRESENTATIVES AND ADVOCATES 3 MR. GELSINGER: It's a very important 4 subject. And I'm very grateful to be able to come in 5 here and represent the subjects of research. 6 I would ask you to not read along with my 7 presentation but just try to follow the slides that I 8 have. Okay? Thank you. 9 Good morning, ladies and gentlemen. I am 10 Paul Gelsinger, President of Citizens for Responsible 11 Care and Research. CIRCARE is a 501(c)(3) nonprofit 12 corporation, the oldest citizen advocacy group 13 dedicated to the effective protection of humans in 14 research. 15 For nearly a decade, CIRCARE has worked to 16 bring the need for major reforms in the protection of 17 humans in research to the attention of federal 18 agencies, legislators, and the public. 19 CIRCARE has an interest in the continuance 20 and improvement of protection of human subjects in 21 research along the lines described in the legislative 22 purpose of this Committee. 8 1 I would like to thank you for responding 2 to our request by giving us this opportunity to share 3 our views with SACHRP. Let me say at the outset that 4 my presentation today is limited in its scope because 5 we were asked for our opinion about the current system 6 of human subject protection under the jurisdiction of 7 the Office of Human Research Protections, rather than 8 to discuss any particular strategies to extend or 9 strengthen the protection of research subjects. 10 It seemed more sensible, however, to 11 describe the conditions in which potential or actual 12 research subjects find themselves, rather than our 13 opinion of these conditions. Matters of opinion are 14 open to endless debate while matters of fact are 15 tolerated or remediated. 16 Society has a moral obligation not to 17 exploit altruistic individuals who willingly serve the 18 public good by acting as research subjects. The 19 current human subject protection system does not 20 effectively protect the rights and welfare of humans 21 in research because it works post hoc. Such 22 compliance efforts as exist are not engaged until a 9 1 subject is harmed or an allegation of noncompliance is 2 made. 3 Acting in response to harm and preference 4 to proactively preventing it is unjust and a poor 5 recompense for subjects' altruistic impulse. 6 The current system does not effectively 7 protect the rights and welfare of research subjects 8 because it relies on the good will of institutions and 9 investigators. Yet, the prestige and ranking of 10 institutions are largely determined by the value of 11 research grants awarded. And investigators depend 12 upon the research grants for career advancement, 13 prestige, and often their salaries. 14 These powerful motivators can conflict 15 with the protection of research subjects. And when 16 they do, they often prevail to the detriment of those 17 research subjects. 18 The current system does not effectively 19 protect the rights and welfare of research subjects 20 because it doesn't create rights for research 21 subjects. Rather, the system gives remedies to the 22 regulator to make the noncompliance stop. 10 1 Practically speaking, this is accomplished 2 through determination letters issued by OHRP. On rare 3 occasions, the agency has suspended an institution's 4 federal-wide assurance. And on equally rare 5 occasions, the Department of Justice will prosecute 6 institution for failure to comply with the terms of 7 NIH awards. 8 The pace is glacial. And the public must 9 wonder that the Department of Justice swiftly 10 prosecuted an NIH supplier of defective mice under the 11 False Claims Act. Yet, prosecution of a case 12 involving human research dragged on for five years. 13 The current system does not effectively 14 protect the rights and welfare of research subjects 15 because it holds the institutions, rather than the 16 investigator, responsible for compliance. And as a 17 result, no consequences befall an investigator who 18 fails to protect research subjects. 19 So far as we can determine, institutions 20 rarely, if ever, impose penalties for failing to 21 protect research subjects. And their refusal to 22 condemn such failures or their silence in the face of 11 1 demonstrable noncompliance is taken as approbation by 2 the public at large. 3 The current system does not effectively 4 protect the rights and welfare of research subjects 5 because even if there was the will to aggressively 6 deter noncompliance and provide proactive oversight, 7 OHRP staff appears to be inadequate given the volume 8 of research. 9 As of February 2005, more than 8,000 10 federal-wide assurances were on file with OHRP. Yet, 11 the Division of Compliance Oversight has six 12 employees. This works out to each employee being 13 responsible for the oversight of more than 1,333 14 institutions and their IRBs. This is perverse. 15 Finally, we know the system does not 16 effectively protect the rights and welfare of research 17 subjects because the same things keep happening over 18 and over again, much like in the movie "Groundhog 19 Day." 20 Although IRB review and approval under the 21 common rule has been required for federally funded 22 research since 1981, OHRP determination letters, even 12 1 today, 25 years later, find that the IRBs cannot 2 reliably distinguish between research and medical 3 care, approve consent forms without the required 4 elements, approve proposed research on condition of 5 revision without ensuring revisions are made, approve 6 proposed research without adequate information, fail 7 to maintain quorums at meetings, fail to review 8 research at appropriate intervals, fail to make 9 required determinations for review of research with 10 children and prisoners, and don't have appropriate 11 standard operating procedures. 12 For their part, some investigators fail to 13 obtain IRB approval, fail to supply material 14 information to the IRB, fail to report unexpected 15 serious adverse events, fail to obtain informed 16 consent, fail to maintain records, engage in 17 questionable subject recruitment schemes, and fail to 18 follow research protocols. 19 Serious noncompliance is memorialized in 20 a letter from OHRP. The institution and investigators 21 excuse themselves. And they're back at it the next 22 day. 13 1 Many people would agree that after a 2 quarter century, institutions and investigators that 3 are unable or unwilling to comply with the common rule 4 should not be conducting research. 5 Moreover, learned advisory bodies make 6 recommendations for improvements in research 7 protection, only to have them gather dust. The Office 8 of the Inspector General identifies problems and 9 proposes solutions. And while everyone accepts the 10 proposals for the most part, nobody implements them. 11 Indeed, some of the troubling issues that 12 drove OIG's attention several years ago appear to be 13 more pronounced today. For example, in 2000 OIG 14 described a number of troubling recruiting practices 15 in industry-sponsored research, of which one was an 16 inducement whereby the order in which co-investigators 17 would be listed as authors in the study publication 18 dependent upon the number of subjects recruited. This 19 practice was recently replicated in an NIH-sponsored 20 trial published in the New England Journal of 21 Medicine. 22 The take-away message from all of this is 14 1 clear enough. The current system for protecting 2 humans in research is ineffective. And since no 3 meaningful improvements have been instituted, 4 investigators, sponsors, and research institutions 5 must prefer that the system remain the way it is. 6 Now I'm going to shift gears a bit and 7 talk about the ways in which our current system of 8 research protection affected my own life. CIRCARE has 9 long been concerned with the adequacy of reporting 10 unanticipated serious adverse events to OHRP, as 11 required under the common rule. 12 This issue is important because failure to 13 report unanticipated SAEs means subjects are 14 needlessly exposed to risk. Failure to report 15 unanticipated SAEs affects IRB review and approval of 16 proposed studies because it prevents the IRB from 17 minimizing the risk to the subjects and may cause 18 informed consent to fail if not disclosed in the 19 consent form. 20 Without doubt, subjects cannot consent to 21 undertake risks which are not disclosed to them. OHRP 22 and FDA administrative actions attest to widespread 15 1 failure to report unanticipated SAEs. 2 If this were not enough, when gene therapy 3 research came under increased scrutiny in 2000 in 4 response to an NIH reminder to institutions regarding 5 mandatory reporting of unanticipated SAEs, OHRP was 6 overwhelmed by more than 900 SAE reports. Compare 7 this to a total of 383 reports made to OHRP during the 8 ten-year period between 1990 and 2000. 9 We appreciate the Committee's interest in 10 SAE reporting to IRBs. And we realize that multiple 11 reports of the same unanticipated SAE reports and 12 expected SAEs can take up valuable time better spent 13 on review and oversight of research. 14 At the same time, however, it is difficult 15 to see how streamlining the reporting of SAEs would 16 affect the pressing problem of investigators who are 17 unwilling to report SAEs, unanticipated or not. 18 If investigators are unaware of reporting 19 obligations or unable to distinguish between 20 anticipated and unanticipated SAEs, it begs the 21 question of why an IRB approved them as investigators 22 in the first place. 16 1 Investigators who refuse to report 2 unanticipated SAEs touches on the largest problem with 3 our current research protection system because no 4 consequences follow upon their noncompliance. 5 Investigators may be encouraged to do the same thing 6 over and over again. 7 My personal involvement in the protections 8 of humans in research began in 1999, following the 9 death of my son Jesse in a nontherapeutic gene therapy 10 study. 11 Many of you may recall that this phase I 12 clinical trial was being conducted at the University 13 of Pennsylvania by the then President of the American 14 Society of Gene Therapists and overseen by the FDA and 15 the NIH's Recombinant DNA Advisory Committee meeting. 16 In other words, this was at one of the most 17 prestigious institutions in the world, conducted by 18 the man at the head of his field, and overseen by the 19 most respected bodies in the United States for this 20 field. 21 Jesse's decision to participate in this 22 safety study was based on his entirely altruistic 17 1 desire to help infants and others born with the 2 homozygous variant of ornithine transcarbamylase 3 deficiency, which is invariably fatal. 4 He was aware there would be no direct 5 medical benefit for him. The experiment was designed 6 to test whether this technology was safe to use in 7 newborns with the worst form of OTC, of which Jesse 8 had the mild heterozygous variant. 9 My son died of a massive immune response 10 four days after receiving an infusion of a modified 11 cold virus that we were told was safe that carried 12 copies of the gene designed to correct his disorder. 13 Unanticipated serious adverse events in a 14 previous dose cohort were not properly reported. In 15 fact, it was at ten times the dose that Jesse received 16 from that cohort. 17 Unanticipated SAEs and deaths of animals 18 receiving test article were not incorporated into the 19 consent form. I cannot tell you if this information 20 would have changed Jesse's decision, but it would have 21 mine. 22 Widely shared ethical principles in the 18 1 common rule demand that this information be disclosed 2 to him in the consent form. Where I once completely 3 trusted the system of clinical research before Jesse's 4 death, I now find myself unable to trust that system. 5 And I am a trusting man. 6 In my attempt to understand the 7 circumstances that led to Jesse's death and as a 8 result of my affiliation with CIRCARE, I have come to 9 understand that, in addition to our troubled research 10 protection system, the integrity of the research 11 enterprise itself has been undermined by several 12 forces. And an enterprise it is. Human 13 experimentation is big business with billions paid out 14 each year to investigators in institutions. 15 The increased volume of research over the 16 last decade or more has exacerbated the tension 17 between institutions and investigators, on the one 18 hand, and the need to protect human subjects, on the 19 other, as financial rewards increase in growing 20 numbers of trials strain the IRB system. 21 Financial conflict of interest contributed 22 to Jesse's death. The principal investigator at Penn 19 1 owned a 30 percent interest in the biotech company 2 that stood to profit should his research show 3 favorable results. 4 This same company owned the patents on the 5 investigator's gene transfer products and procedures. 6 And through the standard material transfer agreement, 7 the University of Pennsylvania owned stock in this 8 company. 9 As a result, the person charged with 10 ensuring the safety of research subjects, the 11 principal investigator, stood to profit from 12 conducting the research. And the entity charged with 13 reviewing and approving the proposed research, the 14 University of Pennsylvania, to say nothing of ensuring 15 that risk to subjects was minimized to the extent 16 possible, also stood to profit from the research. In 17 fact, just about the only person who didn't stand to 18 profit was my son. 19 By allowing the investigator to own a 20 larger percentage of the company than normally 21 permitted, instead of remediation or removal of 22 financial conflict of interest, the institution 20 1 increased it. This actual financial conflict of 2 interest is only a part of the story. 3 The experiment that killed Jesse was a 4 dose escalation study, that one-tenth the dose that 5 Jesse received four consecutive subjects in a previous 6 dose cohort developed liver toxicities that should 7 have stopped this study. 8 The FDA was well-aware of the first two 9 reactions. But, yet, it never did anything to stop 10 this study. They, in fact, allowed two more patients 11 to be treated at that dose cohort level. 12 My questions as to why the researchers 13 were allowed to continue with dose escalation have 14 never been adequately answered. They never resolved 15 the toxicity in the fourth cohort. 16 There were additional serious protocol 17 violations that were not detected and addressed by the 18 FDA or the Penn IRB. Some of those violations were 19 deliberately concealed from the oversight authorities. 20 In February of this year, after nearly 21 four years of investigation conducted with the 22 assistance of the FDA's Office of Criminal 21 1 Investigation, the Department of Justice decided not 2 to file criminal charges against the people 3 responsible for Jesse's death. 4 The civil settlement the Department of 5 Justice offered these investigators and their 6 institutions essentially allowed research on human 7 beings to resume pending retraining and supervision of 8 the investigators. The institutions paid a fine. 9 When I insisted that the institutions 10 would have to publicly acknowledge wrongdoing and 11 release pertinent documents, I was told that this was 12 not possible. 13 Our current system of research protection 14 did not protect my son. Unexpected SAEs went 15 unreported or under-reported. And because nobody 16 detected this, they were not disclosed in the consent 17 form. 18 As a result, my son did not give legally 19 effective voluntary informed consent. Yet, the system 20 obligates both the investigator and the IRB to ensure 21 that he did so. 22 The institution and investigators were 22 1 subjected to the severest penalties the system can 2 muster. Yet, this is inadequate because the 3 investigators would conduct research on human beings 4 again and will do so in a system that lacks the 5 capacity for proactive oversight or the will and the 6 means to enforce compliance. 7 I now question the integrity of the entire 8 system. And I distrust it. In order to restore that 9 trust, we believe that it is critical to respect the 10 dignity of a person as a human being and to preserve 11 his or her autonomy. 12 Practices which constrain autonomy and 13 cause human subjects to become merely the means to an 14 investigator's ends are reprehensive and unacceptable. 15 And the burden imposed on individuals outstrips the 16 benefit of research to society. 17 To finish up, as you might expect, CIRCARE 18 has a number of proposals for the effective protection 19 of research subjects. I would briefly run through 20 them, but my allotted item is almost up. So you have 21 a handout. Please see your handout. It has a list of 22 all of the recommendations that CIRCARE has for 23 1 improving the system. We can go into those in the 2 question and answer period following. 3 I'm going to flash through those slides. 4 We have a lot of suggestions. And there are a lot of 5 good people that have worked out a lot of things that 6 can help the system. What this Committee is working 7 on, what the Institute of Medicine has worked on in 8 the past, all of those things can be incorporated, 9 pulled together. And we can make a much better 10 system. 11 In closing, remind yourself once a day 12 that research subjects depend upon you to stay alive. 13 Put teeth in the regulations by supporting a system 14 for protecting research subjects that is codified in 15 law. 16 That's not going to be easy to do. There 17 is a lot of resistance to this from the industry side, 18 from academia. They're very resistant to change 19 within the system. But we really need to do it. 20 The people at CIRCARE and I as Jesse's 21 data optimistically await effective protections of 22 humans in research. This picture, there is a little 24 1 story behind this picture. On Jesse's left wrist, you 2 can see a bandage. This picture was taken a couple of 3 hours after he was tested at the University of 4 Pennsylvania to see if he could participate in that 5 clinical trial. This was about three months before he 6 actually went to Penn and participated. 7 He was very optimistic about what he was 8 doing. He was going to battle against his disease and 9 going to help others less fortunate than himself. 10 We need to protect our heroes and make it 11 so that we don't have another tragedy that damages us 12 all. We owe that much to Jesse and more. 13 Thank you. 14 (Applause.) 15 CHAIRMAN PRENTICE: Thank you, Paul. I 16 have heard your talk many times, and it is always very 17 moving. And Jesse has become a hero to us all. 18 We are going to take the panelists again 19 slightly out of order. I'd like to invite Bob Huff to 20 come up. And while he's doing so, I will read 21 extracts of his bio. 22 Bob Huff is the Editor of the GMHC 25 1 Treatment Issues, the HIV treatment, research, and 2 policy publication of the Gay Men's Health Crisis in 3 New York, which is the oldest and one of the largest 4 AIDS service organizations in the world. GMHC is 5 committed to providing compassionate care to New 6 Yorkers with AIDS. 7 Mr. Huff began working in the field of 8 experimental HIV treatment information and activism as 9 a member of the Treatment and Data Committee of ACT UP 10 in New York in 1987. He has a long involvement in 11 this particular area. And we are delighted that he 12 has agreed to come and speak with us today. 13 Welcome, Mr. Huff. 14 DR. HUFF: Thank you, Dr. Prentice. 15 I am kind of doing this on the fly. So 16 please bear with me. It's very nice to be here. It's 17 very nice to be in a place where I can have grits for 18 breakfast. 19 (Laughter.) 20 DR. HUFF: Let's see. I think that in 21 HIV, AIDS, research has gone hand in hand with the 22 response and care from the very beginnings because it 26 1 was such a mystery and no one knew what was going on. 2 So efforts to find out what were going on 3 arose immediately. And community involvement through 4 participation and volunteering and those efforts began 5 almost immediately. 6 And the motives that I think Jesse had are 7 -- you know, I've heard those same things. And that's 8 very familiar. The altruism, the need to fight back, 9 to do something. And it's still true for many people 10 who participate in research. 11 Now there are many other motives I think 12 that come into play. And I'll get to those later. I 13 just wanted to say that I have never been in a 14 research trial. Fortunately, I don't have to take the 15 drugs. My role here I think today is kind of a 16 critical observer maybe. And I'll just try to report 17 what I have seen over the years. 18 In June of 1981, AIDS was first reported. 19 And almost immediately, there was a community 20 response. GMHC was formed within a year. A group of 21 people with AIDS, People Living with AIDS, PWAs, met 22 in Denver 1983 and established some principles for 27 1 what they thought should be the involvement of people 2 living with AIDS and all aspects of decision-making 3 that affected their 4 Lives. And they did touch upon research, 5 including the right to full explanation of all medical 6 procedures and risks and the right to choose of refuse 7 without jeopardizing their treatment and critically 8 the right to make informed decisions. 9 You know, we have tried to build into 10 subsequent research efforts and the structures that we 11 built. Almost immediately AIDS treatment activism 12 emerged. People formed information groups. And 13 formally they began publishing. AIDS Treatment News 14 was one of the first publications that was reporting 15 on what anybody heard. 16 A lot of this was just rumor and anything. 17 People were grasping at straws. Buyers' clubs would 18 fly off to Israel or France or go down to Mexico and 19 buy things that they had heard might work and bring 20 them back. So there was a real community for the 21 community response. 22 This is because in the gay community at 28 1 least, there was a community. And it had a history of 2 political organization through the struggle for gay 3 rights. And then I think the health aspect came in, 4 especially later on. The women's health movement in 5 the '70s fed and informed the response, too. 6 But also many of the people first affected 7 by HIV were privileged individuals, upper middle class 8 urban dwellers. And they had access. They could call 9 up doctors and researchers, find out what was going 10 on, what was the latest information, and jet off to 11 Paris, like to get the latest treatment. They funded 12 and helped some of these organizations become 13 established. 14 Yet, the fact was none of these treatments 15 were really doing much at all. And as the death toll 16 grew and grew and just all through the '80s, the 17 horror grew, the desperation and the rage grew. 18 In 1987, an organization called ACT UP was 19 formed. The model was to take direct action to end 20 the AIDS crisis in many issues, but they were 21 responding primarily to slow research, unnecessary 22 research methods, ignorance, high prices, and that 29 1 techniques were making demands, having demonstrations, 2 garnering publicity. And some of the actions were -- 3 this photograph is from an action, a dye-in at Wall 4 Street in 1987. 5 In 1988, we surrounded the FDA 6 headquarters in Rockville and had a day of it. In 7 1990, the action was a Storm the NIH. These were our 8 version of a determination letter, let's put it. 9 (Laughter.) 10 MR. HUFF: But the protests were 11 effective. The protests did produce change. FDA did 12 speed up drug approvals. There are a couple of 13 examples. 14 Dr. Fauci met with the community and 15 supported parallel track. And that was to give people 16 access to drugs in parallel while they were still 17 being evaluated in clinical trials. The initial very 18 high and rather toxic dose of AZT was cut in half. 19 NIAID invited -- well, they didn't invite 20 us. First, we had to kind of crash the AIDS clinical 21 trial group meetings. But the next one we were 22 invited. 30 1 (Laughter.) 2 MR. HUFF: And subsequently that has grown 3 into an integral part of ACTG, which is the community 4 advisory boards. And people are involved at all 5 levels of protocol evaluation and meetings on how 6 slowly everything is going. Expanded access programs, 7 this was a collaboration, really, between FDA and 8 industry and academic researchers. 9 Back up. Now, one of the key struggles 10 that came up was what I call access versus answers. 11 And there was a strain in the community. They 12 absolutely wanted access to drugs all the time, all 13 drugs all the time. And that manifested in something 14 called Compound Q, where people organized a research 15 of this protein from a Chinese cucumber, I think. My 16 memory is dim at this point. 17 This was done in apartments in New York 18 City and in San Francisco. And some people died from 19 it, we think. Some people are still alive today and 20 doing well. We have no idea what, but it was a 21 frightening episode, I think, for a lot of us because 22 we didn't know what this stuff was and what they were 31 1 doing on the other side. 2 But the reality was that clinical trials 3 offered the only access to some life-saving 4 treatments. But we wanted to know what works. In ACT 5 UP, we had the Treatment and Data Committee. And we 6 started teaching ourselves. 7 We started reading these protocols and 8 educating ourselves, published a directory of clinical 9 trials in New York, New Jersey, and Connecticut area 10 because we wanted to make people aware of what was 11 available out there. 12 But in doing that, we would critically 13 read the protocols. And if we didn't like what we saw 14 or we saw something was unfair or unnecessary, we 15 would definitely engage on that issue. And we 16 subsequently analyzed the NIH and research methods and 17 the politics and the economics, I should say also, 18 behind a lot of these, what was motivating the 19 research of certain therapies and not others. 20 We were very fortunate to actually early 21 on be mentored by some heroes. And one of them was a 22 man named David Beyers from the National Cancer 32 1 Institute, who had earlier worked on sort of debunking 2 the laetrile cancer cure. 3 And he was living with AIDS and was very 4 interested and heard what we were doing and actually 5 sponsored a meeting and brought us together with NIH 6 people. And it was a very interesting meeting. But 7 he took us seriously and actually saw in some of the 8 things, we were asking a lot of practicality. 9 Susan Ellenberg from NIAID, who is a 10 biostatistician, was very instrumental in introducing 11 us to people and getting people to really chew on what 12 it is we were asking. And biostatisticians turned out 13 to be really critical because they sort of held the 14 keys to what constitutes truth, you know, what 15 constitutes believable convention and data. And they 16 were critical of a lot of things that we were critical 17 of. 18 Let me look quickly. We began to develop 19 this public health perspective. And our concerns with 20 safety grew, too. So we wanted to know what was in 21 the stuff because at the same time, industry, you know 22 -- it wasn't a great gift to us, the speed-up of drug 33 1 approvals. There were other powerful motivators in 2 that the drug lobby was also very interested in 3 speeding up approval times. 4 So we had some wind at our backs. So we 5 began to realize that we had to be critical of the 6 industry's methods and data, too. And in the early 7 days, we learned the tricks pretty quickly and began 8 to expose them. And things are much better now. 9 There were issues that we started working 10 on very early that are still with us. And I just want 11 to say we're talking about human subjects, but I'm 12 talking about patients, people with AIDS, consumers, 13 whatever, and the blurring between the two because so 14 early on, they just seem to be the same and would flow 15 from one to the other. 16 But enrolling people in clinical research 17 from the affected populations is an early demand and 18 still not satisfying. Enrolling enough women in 19 clinical research is still tough. A new drug was 20 recently approved, maybe 10 to 15 percent 21 participation of women in the study. And there are 22 some particular toxicities that probably affect women 34 1 more. And it's really, really frustrating 2 continually. 3 The community actually opposed some 4 research at one point in the interest of protection. 5 And, unfortunately, we were -- well, not me but others 6 were wrong about this because it turned out that these 7 studies were very crucial. And their results that 8 they produced actually changed, sort of changed 9 history. 10 In the meantime, industry is developing 11 new drugs. And about 1995, everything changed. As 12 you can see from here, this is what happened to 13 mortality after the introduction of combination 14 therapy with what's called HEART, highly effective 15 antiretroviral therapy. 16 And it was dramatic. It was felt on the 17 street, and it was felt among our friends. We went 18 from being in hospitals and watching our friends die 19 every month or so. And it became a very rare event, 20 although it still goes on. I now lose someone maybe 21 once a year, but it's a dramatic change. 22 And so our role began to change after 35 1 this. And it's always this ever-moving target of the 2 risk-benefit analysis, I think. With 22 drugs or more 3 approved in the U.S. -- I'm losing count -- and many 4 interesting new generation drugs on the horizon, there 5 are still some scary drugs. 6 This last drug to be approved is not for 7 everybody, but it is going to save the lives of the 8 people for whom it is for. But we have to make sure 9 that it is not inappropriately promoted by the 10 pharmaceutical company. And there is this constant 11 battle that goes on. 12 Let's see. You know, people participate 13 in research for many reasons. An altruism, wanting to 14 fight the disease, is a key one for many people. But 15 for a lot of people, that is where they get better 16 care. 17 I know people in community groups who just 18 encourage people to get involved in research because 19 the care they are going to get is going to be much 20 better than what they get through their Medicaid 21 clinic. 22 It is still a case where people who have 36 1 multiple drug resistance, salvage patients they are 2 known as, that the only way they can get access to a 3 life-saving drug is through research. So that's a 4 smaller proportion of people now, but it is still 5 absolutely critical for them. 6 A lot of people participate because maybe 7 they have been involved in the ACTG CABs, community 8 advisory boards. They're very familiar. And they're 9 comfortable with their researchers. Some people say 10 it's Stockholm syndrome, but there is a community of 11 people who are always willing to show up and help. 12 We continue to watch and report on what is 13 going on. I think FDA advisory committee hearings are 14 incredibly important to report on because things 15 appear at those meetings that never appear in the 16 label. And the emphasis is shifted or the concerns of 17 the advisory panel members never really get translated 18 outside of that room. So I always try to report on 19 what happens at those meetings. 20 There is a group that brings together 21 industry and academia and researchers to sit down 22 together in kind of a closed-door setting and hammer 37 1 out issues. 2 The FDA, I have had tremendous admiration 3 for them. At least the people I know, the Antiviral 4 Division, -- I'll put a bracket around it because I 5 know nothing about Vioxx -- at least the world that I 6 know -- and maybe it's Stockholm syndrome, but they're 7 really sharp. They have really worked hard to find 8 this balance, this ever-changing balance. 9 And between making drugs available as soon 10 as practical, as soon as they can be safely made 11 available, and getting the answers and raising the bar 12 -- every new drug the bar gets raised for HIV. And 13 I'm really impressed. 14 I think their willingness to talk to us 15 and educate us and communicate, it's public service to 16 the highest order. And I'm very happy they're there. 17 I just want to jump back at the problem of 18 enrolling women in trials. I mean, this is an 19 historical problem in that women were to be protected 20 and not put in clinical trials up until '93, I think, 21 when that policy changed. But the unintended result 22 was that drugs were being released to be used in women 38 1 without having them tested in women. And they're 2 finding out some serious toxicities later on. 3 Nevaripine is a good example of that. 4 Continuing suspicion of research, the 5 Tuskegee legacy, which probably contributes to the 6 continued low enrollment of people of color in 7 research, not the only reason but one. And, yet, now 8 we're seeing drugs that actually have different 9 pharmacokinetic responses in some people of color and 10 which may manifest in some more toxicity or it's 11 vague, but these are issues that have to be looked at. 12 Let me get to some current issues that are 13 floating out there right now. In Europe, my 14 counterparts have recently become very focused on 15 protection of human subjects, Helsinki declaration and 16 application of ethics, what I think is a rather 17 legalistic reading, but they forced some policy 18 changes on use of drugs in people who are 19 treatment-naive, yet at very low susceptible immune 20 state. They're concerned that people will be 21 inappropriately enrolled in trials, that there are 22 inducements for investigators to enroll these people. 39 1 And they have a really good point. And there may well 2 be. 3 On the other hand, this is a class of 4 drugs that is probably going to be widely used in 5 people without prior experience, treatment experience. 6 And, again, it's tension that do we need to test the 7 drugs in the populations in which they'll be used so 8 we know what is going on. The FDA has sort of taken 9 the position that they should be studied in all 10 populations. 11 Some currently things that are in the use, 12 this drug tenofovir, an oral drug that is taken for 13 pre-exposure prophylaxis. And there are some clinical 14 trials set up to test this in very high-risk 15 populations: sex workers in Cambodia, drug users in 16 Thailand. 17 The consultations with the communities 18 were not well-done. The informed consents probably 19 weren't very well done. You know, I've really come to 20 realize talking to researchers that it seems like the 21 issue of ethics has to be an ongoing struggle. 22 It's not enough to simply have your 40 1 informed consent translated into the local dialect and 2 leave it at that. You have to work at it and work at 3 it and work at it. 4 On the other hand, it's not as simply as 5 just holding up the Helsinki declaration and pointing 6 to a principle and saying, "This is the law." It 7 really has to be struggled with. That's my conclusion 8 as of today. 9 There were some demands made. The trial 10 in Cameroon was stopped. There are policies, U.S. 11 policies, that, actually, I believe are putting the 12 subjects at risk. The tenofovir prevention study in 13 Thai drug users is probably not going to continue. 14 This is potentially a very important intervention, but 15 it's mostly agreed now that it's not ethical to not 16 offer the best available prevention to people in a 17 study, in a prevention trial. 18 You really have to give them counseling, 19 education, and if there is any kind of prevention 20 intervention available, you have to give it to them. 21 Well, the one that works is clean needles. And U.S. 22 won't buy clean needles. So this trial is probably 41 1 going to crash pretty soon. 2 In Cambodian sex workers, the background 3 is not as clear to me as the facts are still coming 4 out, but the consultations with the community were not 5 well done. 6 Some groups that had been working with 7 this community is funded by U.S. AID I think were 8 pulled out because they were no longer allowed to 9 engage in a meaningful way with sex workers because 10 they were U.S. funding restrictions. That trial is 11 stopped. This is potentially an incredibly important 12 intervention that is going forward. 13 More ethics and policy. There have been 14 some recent news reports. In fact, I just saw 15 something this morning about NIH whistleblower and 16 nevaripine studies, the HIVNET ON2 studies in Uganda. 17 It's all coming from pretty much one reporter. And it 18 makes an easy target. I've seen people jumping on 19 this for political sound byte purposes. 20 It doesn't seem to be about what it is 21 really about. And with NIH authorization up in the 22 air, one can make all sorts of -- be suspicious about 42 1 the real motives behind some of these attacks. 2 There's a news story about, which I'm sure 3 you'll be delving into, the Incarnation Children's 4 Center, New York City, where children were 5 inappropriately enrolled. The story has yet to be 6 told. But, again, the same reporter is on it. 7 This time this story has really been 8 brought out by people who don't believe HIV is the 9 cause of AIDS. And to them the crime is really giving 10 any treatment to these children with HIV, not so much 11 that the particular practices -- it's a very 12 confusing, horrible mess. 13 And, unfortunately, the public sees these 14 op. ed. pieces. There was one today from a Southern 15 newspaper that just calls for complete turning over to 16 the NIH and cleaning house and cleaning up this mess. 17 And that's what the public sees. 18 It's caused a lot of harm because, 19 frankly, these stories leave the U.S. They go around 20 the world. They create suspicion, feed prejudice. 21 And you can't call them back. 22 So between the motives of the 43 1 whistleblower and the denialists, I think there is 2 some nasty stuff about reflected in these myths, some 3 of the popular myths. These myths have slowed 4 treatment efforts in South Africa. The President of 5 South Africa doubts that HIV is the cause of AIDS. 6 But, to counter this, this principle of 7 community involvement, of educating yourself, of 8 preparing for treatment of becoming scientifically 9 literate, treatment literate is spreading around the 10 world. And one of the biggest proponents has been the 11 Treatment Action Campaign in South Africa, very 12 well-organized. It goes into townships, educates. 13 And you have situations where people know 14 because they have posters, they have palm cards, 15 t-shirts that talk about the drugs, even before the 16 drugs are available. But they will know the drugs. 17 They know what they do. They know what they don't do. 18 They know the side effects. And this is remarkable. 19 And I think this is the model that we're trying to 20 promote and bring to India. And it's happening in 21 Thailand slowly, and I think it is a very positive 22 thing. 44 1 So just quickly to wrap up, there are some 2 issues out there. I was trying to think of, well, 3 what are we not paying attention to. We never really 4 see protocols for first use of a drug in humans. It's 5 sort of under cover. It's done in private facilities, 6 paid volunteers. 7 I hear increasingly these are moving to 8 eastern Europe and places even more out of sight. So 9 if all goes well, we hear about the drug. If it 10 doesn't, we never really hear. I don't know what kind 11 of oversight the IRBs in these cases provide 12 effectively. 13 We're hearing about more trials in eastern 14 Europe and Russia and China. I think someone has to 15 pay more attention to these because they do not have 16 the history of respect for the individual, respect for 17 the patient. The principle of informed consent is 18 glossed over. And I think that needs a lot more 19 attention because I have heard some horror stories 20 from these regions, in particular. 21 Contract research organizations also are 22 hired to do the research. It's one step removed from 45 1 accountability, at least in terms of we can go to the 2 company and hammer them and make them show us stuff, 3 but if it's out of their hands and they're being told 4 a story by the CRO, then they're telling us that they 5 have been told. And we don't know. So that's one 6 step removed from observation. 7 Anyway, I think the idea is to always have 8 informed involved independent community participation 9 in all the decisions from the development of the 10 protocol forward. 11 The next best is just to have 12 transparency. I think within HIV, we have a good 13 amount of transparency. I was going to maybe digress 14 a little bit on what I think. You can see what I 15 think is special about HIV. And I don't know that 16 much about other disease groups. 17 At some point, we had breast cancer 18 activists from Long Island visit us in the mid '90s. 19 And they were great, you know. But I don't know how 20 it translated into that movement. But, you know, 21 there was so much potential for learning from each 22 other. 46 1 But we don't want to go back to that 2 glacial pace of developing new drugs because people 3 are still dying. It's all over the world 40 million 4 affected and 83 million dying per year. We still 5 desperately need HIV treatments. 6 Thank you. 7 (Applause.) 8 CHAIRMAN PRENTICE: Thank you, Bob, for a 9 very interesting overview of the evolution of 10 treatments developed for HIV-affected individuals. 11 I would like to now call upon Maria 12 Carolina Hinestrosa. And while she comes up to the 13 table, I will read extracts of her bio. 14 She is the Executive Vice President for 15 Programs and Planning at the National Breast Cancer 16 Coalition. She is also co-founder of a support 17 network for Latinos with cancer in the Washington 18 metropolitan area. 19 She is a member of a number of different 20 groups; for example, Chair Emeritus of the Integration 21 Panel of the Department of Defense Cancer Research 22 Program. She also serves on various national 47 1 committees at the NCI, Institute of Medicine, the 2 National Quality Forum, and others. She was also a 3 Fulbright scholar and holds graduate degrees in 4 economics and public health. 5 Welcome. And we're delighted that you 6 would take the time to address us. 7 DR. HINESTROSA: Thank you very much for 8 the invitation. Even though it wasn't planned that I 9 would speak last, I think it is actually a good 10 sequence because I will be able to answer one of the 11 last questions that was asked, about how the HIV 12 movement or AIDS movement inspired the breast cancer 13 movement. So I am going to provide some of that 14 overview. 15 I, of course, want to thank the panel for 16 inviting me and speak about the experience in the 17 breast cancer community and the work that we are doing 18 and how we are approaching these issues of patient 19 participation and consumer involvement in the research 20 process. 21 The National Breast Cancer Coalition was 22 formed in 1991. And, actually, it was inspired by the 48 1 activity and the successes and the activism around 2 HIV/AIDS. And so even though other organizations had 3 been formed prior to this geared to support people 4 affected by breast cancer, it was felt that it was 5 very important to have a group focus on political 6 change and systems change so that we could really 7 advance in breast cancer. 8 At the time that the coalition was formed, 9 only $90 million were spent every year on research for 10 breast cancer at the federal level. And we felt that 11 that was unacceptable and that this is a disease that 12 was affecting over 200,000 women each year. And so 13 action needed to take place. 14 Today, the National Breast Cancer 15 Coalition is a coalition of hundreds of organizations 16 and tens of thousands of individual members. The 17 mission of the National Breast Cancer Coalition from 18 the beginning, 1991, has been to eradicate breast 19 cancer, to end the disease through action and 20 advocacy. 21 The way we do our work -- and our focus is 22 on research access and influence. Key to all of our 49 1 work is the influence of consumers. 2 I looked at the question, of course, that 3 were given to us to sort of help us frame our remarks 4 today. I'm going to try to go through those. And 5 some of the questions have to do with the specific 6 issue of patient protections but also on the issue of 7 consumer involvement. 8 So just before I do that, I just would 9 like to tell you a few of our proudest accomplishments 10 in the breast cancer movement through the National 11 Breast Cancer Coalition. 12 Key to our work has been the increasing 13 federal funding for breast cancer research. And we 14 focus an increasing federal funding -- and our 15 strategy is federal funding because we believe that 16 you need substantive amounts of money to really 17 address this disease. 18 So we started with pushing for increases 19 at the NIH level but also created what is now the 20 Department of Defense Breast Cancer Research Program. 21 That program alone has brought close to two billion 22 new dollars into breast cancer research. And I will 50 1 tell you a little bit more about how that works later. 2 We also developed a system of care for 3 uninsured women who are diagnosed with breast and 4 cervical cancer through the CDC screening program. As 5 some of you may know, that program was created over a 6 decade ago to screen women for breast and cervical 7 cancer. 8 And then when they were diagnosed with 9 breast or cervical cancer, they were pretty much left 10 on their own to try to find treatment or through a 11 network of charity organizations, which became 12 increasingly strained. 13 And the coalition believed that that was 14 not good public policy, that if you were going to have 15 a screening program, you needed to have treatment. 16 And we were after political activism able to get an 17 expansion of Medicaid to offer treatment for those 18 women. 19 We also created an educated grass roots 20 network of activists, survivors, and patient 21 advocates, who are making decisions every day about 22 research, about quality care, and about public policy. 51 1 So how do we view the participation of 2 consumers and patient advocates in research? Is it a 3 benefit or does it give benefits or a threat? 4 While we very strongly believe that 5 consumer participation is essential, it is essential 6 that well-informed, educated consumers participate at 7 every level where decisions are made about breast 8 cancer. Of course, our focus is on that disease. 9 We believe that that involvement needs to 10 be meaningful and that that meaningful involvement is 11 going to result in a system that is transparent and 12 that is accountable, that it is accountable to its 13 primary stakeholders: the patients. 14 Consumer involvement we believe forces 15 innovation by challenging the status quo. And as we 16 participate and not only seated at the table but 17 participate in a meaningful way alongside the 18 scientific community and policy-makers. We are people 19 who bring the interest of, again, the community most 20 affected by the disease. And so we believe that that 21 allows us to ask sometimes what people call the dumb 22 question, which, in fact, leads to breakthroughs in 52 1 ways of thinking. 2 So our approach is to educate consumers. 3 We have created a program known as Project Lead. 4 Project Lead is a science course for consumers for 5 survivors and patient advocates to give those 6 participants the language of science and understand 7 the research process and understand the concept of 8 science that will then enable us to participate in 9 working alongside the research community on issues of 10 breast cancer research. 11 After we ran Project Lead for several 12 years, we created an advanced course; that is, 13 Clinical Trials Project Lead. Clinical Trials Project 14 Lead trains consumers to then participate and work 15 with research organizations on designing clinical 16 trials; monitoring clinical trials; helping critical 17 trials; and, again, looking at critical trials, having 18 a closed participation in that system bring in the 19 patient perspective. And we also developed a quality 20 care project lead which is still in its pilot phase. 21 We have trained over 1,200 consumers 22 through these programs. These programs give really 53 1 the principles of evidence-based care and 2 evidence-based medicine, which guide a lot of our 3 work. 4 Through that system of education, then, we 5 can help consumers aspire with the scientific 6 community to develop research projects, to develop 7 research mechanisms, to evaluate proposals, to make 8 funding decisions. 9 By doing this, we define and frame the 10 issues in patient-centered terms. So we have 11 developed the National Breast Cancer Coalition. You 12 can find those on our Web site, principles for 13 research from a patient-centered perspective. 14 We have developed core values for quality 15 care. We have defined from our perspective what 16 quality care is and are working on changing the 17 system, educating consumers, developing demonstration 18 projects that will lead to improvements in our system 19 of care. We have also developed research 20 partnerships. And I will explain some of those later 21 on. 22 Part of our approach also is to develop a 54 1 public policy agenda that immobilized our members and 2 our consumers to implement that agenda and promote 3 systems change at every level. I talked already about 4 some of the research work that we are doing but also 5 working with different players in the system. 6 We also have worked with the private 7 sector to change systems at that level. And then that 8 involves not only developers of interventions for 9 breast cancer in the pharmaceutical industry but also 10 third party payers of health care. 11 Now, the question as to what is our 12 current level of involvement in the research process, 13 we are doing this in two different ways: first of 14 all, working to influence research at the federal 15 level but also working to influence the research 16 agenda at the private level. 17 With the DOD Breast Research Program I 18 mentioned before, it's over two billion more dollars. 19 What we have done with that program is really create 20 a new system of research where consumers are at the 21 center and participate at every level, from designing 22 the research mechanisms to participating in peer 55 1 review as peer reviewers. 2 People have been trained to do this, to 3 look at a protocol and look at whether this is 4 important research, this is innovative research, but 5 it is relevant to this. 6 Often we find research proposals that are 7 beautifully written, elegant research, but they are 8 proposals that will keep some very bright researcher 9 doing very elegant work. Will it have an impact on 10 people with the disease? Unlikely. 11 And so those very highly scored proposals 12 often don't get funded when you find other research 13 that really is moving us closer to our goal. 14 So it has had a profound impact in the 15 cancer field in general, not just breast cancer. 16 Those of you who are familiar with the cancer world, 17 not only there are other programs that are modeled 18 after the DOD Breast Cancer Research Program, but now 19 the involvement of the consumers at the research table 20 has become commonplace. We are still hoping to have 21 more meaningful input into the NCI process and are 22 working towards that. 56 1 Recently, in June, we had the third or 2 fourth report to the public on the work of the DOD 3 Breast Cancer Research Program. We insist that there 4 is public reporting and there is a meeting. This one 5 was in Philadelphia. 6 Just to give you a few numbers, at this 7 scientific meeting, there were about 1,800 people. 8 Everyone who has been funded by the program over the 9 period of time between those meetings is obligated to 10 come and present. Whether the results are what they 11 expected to be, whether the results are negative, 12 whether the results are inconclusive, everyone is 13 obligated to present a poster to report to the public. 14 And also, of course, there are symposia, plenaries, 15 and all of that. 16 There were 270 consumers who had 17 participated in peer review over the prior three years 18 who were invited to participate in the meeting and be 19 there, participate in the sessions, ask questions of 20 those researchers. 21 Those 270 consumers represented over 90 22 different organizations that are related to or work in 57 1 the breast cancer field. So it is clearly a system 2 that allows us to have, again, that transparency and 3 accountability. 4 And also the meeting was designed between 5 scientists and consumers. And so we had every session 6 that was planned for the meeting was co-chaired by a 7 consumer. 8 We also participated, as was mentioned 9 under my bio, with different and many government 10 committees or government-convened committees to look 11 at different issues of relevance, of course, to breast 12 cancer and to patients in general. 13 So they are IOM committees. And the IOM 14 Committee on Patient Protections is one where Fran 15 Visco, President of the National Breast Cancer 16 Coalition, was a member. And I have participated. I 17 have been the one consumer in a couple of those IOM 18 committees. 19 I think it is very important to have 20 consumers. I hope that in the future, we have more 21 than one consumer who really can bring that important 22 perspective and really have an influence on the 58 1 conduct of the committees' work and also on the 2 recommendations. 3 The second part of my answer to what level 4 we are involved is, again, working with the private 5 sector. In our interest in improving the research 6 process, we have developed a set of research 7 partnerships for which our board of directors 8 developed a policy. 9 And so the goal of our clinical trials 10 partnership really is to improve trial design, to 11 monitor and monitor to increase access and accrual to 12 innovative research, to educate the medical community 13 and consumers about that research, and to promote the 14 initiation of high-quality breast cancer trials. 15 We find that there are so many clinical 16 trials out there. And our concern is also much that 17 there aren't enough clinical trials. There are too 18 many clinical trials. There are too many wasteful 19 trials, unnecessary trials. And we need much better 20 coordination and really access to truly important and 21 innovative trials so that we really move forward in 22 our goal to end this disease. So this is why we 59 1 created this clinical trials partnership program. 2 So what do we do? The criteria that we 3 utilized to engage -- and we get approached very 4 often. Many companies come to the National Breast 5 Cancer Coalition to say, "Well, we have this great 6 thing. Will you participate? Will you help us accrue 7 patients? This is the protocol." 8 And we say, "Too late. If you want to 9 work with us, you need to come early on because we 10 want to sit at the table and work with you to help you 11 design a clinical trial that is going to have an 12 impact and that is meaningful and that asks an 13 important question that is well-designed that has 14 meaningful and important endpoints. 15 So our criteria is that the trial needs to 16 be designed to answer an important and novel question 17 that the study must be well-designed, must be 18 scientifically rigorous and employ appropriate and 19 meaningful outcomes that must be conducted in an 20 ethical manner. 21 There must be sufficient data supporting 22 the potential efficacy and safety of this intervention 60 1 and that there needs to be sufficient information to 2 provide meaningful information to the potential 3 participants in the study. 4 There need to be safeguards for patient 5 privacy. There, of course, need to be the necessary 6 IRBs and data safety monitoring committees for the 7 trials. Also, the cause for patient participation in 8 the trial and the care need to be covered, inclusion 9 of diverse populations and also our expectations. 10 Our expectation is that we will 11 participate informally and in formal ways to give 12 input towards the design, who will participate and 13 help with outreach for the trial. 14 We insist, we absolutely insist, that the 15 results of the trial, negative or positive, be public, 16 be made public, and published. And we will help 17 getting that information to out networks. 18 We will help organizations develop to 19 expand access and compassionate use programs and also, 20 again, as I said before, that we help with the 21 dissemination of the results. 22 In return, we will give the organization, 61 1 again, that input. We will also insist that we have 2 representatives on the data safety monitoring boards 3 and the steering committee for the trial. And we will 4 insist that patients be given information as the trial 5 is ongoing. This information on our approach to this 6 is on our Web site. 7 Some examples of trials in which we have 8 participated are, for example, the herceptin pivotal 9 trial that was conducted many years ago. And, again, 10 it was the monoclonal antibody targeting a specific 11 population with a very aggressive type of breast 12 cancer. 13 It was innovative. It was a program that, 14 in fact, when the company began doing this research, 15 it was having a lot of difficulty accruing for the 16 trial, keeping things intact. They came to us. They 17 said, "Well, there are many things that are not 18 happening right here. You need to really work with 19 us." 20 We helped them design the program. We 21 helped them design the expanded access to 22 compassionate use creating a lottery system to really 62 1 avoid favoritisms. And it was looking like the trial 2 was going to really meet its endpoints, but there was 3 a lot of concern about access and people wanted to get 4 access to this drug very quickly before we had really 5 the information that was necessary. 6 And that was a very positive trial. And 7 then recently, of course, this year we have 8 information that, in fact, that drug has this 9 incredible impact in the adjuvant setting. 10 So that was a very important success. And 11 we are still working with them on a Phase III trial 12 for the adjuvant setting, trial. But then we have 13 worked in other trials that have not had positive 14 endpoints, like there are vaccine trials. We had the 15 elastin trial, which is a drug that more recently 16 another study found important impact in a different 17 setting, a metastatic setting. 18 But in any case, it has been really 19 focusing on innovation, on new approaches, on 20 approaches that will have the promise to have really 21 a major impact in breast cancer. And this is when we 22 will put our resources together to help a company. We 63 1 do not accept any money. We don't ask them to pay for 2 our work around those trials. It is really, then, of 3 our own resources. 4 We also in working with industry and 5 really with the community in general convened 6 consensus meetings at some think tanks that look at 7 key issues in breast cancer, in public policy, in 8 research to really help us, again, use the scarce 9 resources that we have and really help us save lives, 10 save money, and use our time better. 11 We bring stakeholders' focus on those key 12 issues. We're going to have a meeting, a consensus 13 conference, strategical consensus conference, 14 biomarker research in breast cancer, to really see 15 what we can do to ensure clinical relevance. 16 There's billions of those that are being 17 poured into biomarker research. And no one seems to 18 know sort of what to do with this. And so we're 19 bringing different groups of stakeholders into the 20 table to really develop a strategic plan and help us 21 move forward. 22 The last point that I wanted to just 64 1 discuss was -- well, the last question that was sort 2 of posed to me was what do we think of our current 3 system of patient protections. Do we believe it is 4 too reckless, too cautious? Is it properly balanced? 5 We believe that the current system that we 6 have, the current IRB system, doesn't offer enough 7 protections to patients. The system is over burdened. 8 It's inefficient and lacks the adequate consumer 9 participation. 10 One issue of great concern to us and the 11 one that is really integral to the system that we have 12 in the United States is that, really, we have our 13 system of health care incentivized by, really, profit. 14 And so many of the places in the system -- 15 because we have a fragmented system of care, there are 16 many places. And many of those places are accountable 17 to their shareholders, to their owners, to whatever. 18 But, in fact, we believe that the profit motive was 19 essential to our overall American way of life puts the 20 patient in a vulnerable position. So we need to be 21 extraordinarily careful given that that is how our 22 system operates to protect patients from those 65 1 motives. 2 It is, therefore, very important that we 3 avail consumers of the information and all the 4 information that is available and not only that but we 5 involve consumers in decision-making so that they can 6 meet accountability. 7 We see this practice as an art and not 8 often enough is evidence-based. This is why the 9 National Breast Cancer Coalition works so hard to 10 educate and empower consumers to understand the limits 11 of the practice of medicine and to understand the 12 principles of evidence-based care and also to 13 understand what scientific research does and doesn't 14 do and critically analyze the research that is being 15 conducted and published. 16 The other issue that is of concern is that 17 just given the system that we have, researchers, yes, 18 many and I would say most of them do work having the 19 concerns of patients in mind, but we also have a 20 system that rewards publication. And so the first to 21 publish is the person that gets the most prestige. 22 And so in that rush to be the first to 66 1 publish, to publish anything or to just come up with 2 a result, also the patient becomes vulnerable. And so 3 this is why also consumers need to be involved in 4 participating with the scientific community at all 5 levels. 6 So what do we need to do? What actions 7 need to be taken? We believe that the recommendations 8 of the IOM Committee on Patient Protections need to be 9 implemented. And they, of course, recommend that 10 there should be three aspects to the review of 11 research proposals that include scientific review, 12 financial conflict of interest review, and ethic 13 reviews. That is critically important, and it needs 14 to happen. 15 We also need to be sure that we revitalize 16 because in process to engage patients and disclose and 17 exchange information, this is also part of the IOM 18 committee to ensure that the focus is really on 19 informing participants and not on protecting 20 institutions. 21 I participated on IRBs where so often an 22 informed consent form was really a legal document 67 1 protecting an institution and not really something 2 geared to inform patients and really, again, protect 3 them. 4 And so the IOM really is recommending that 5 we don't call this informed consent but consent 6 because we just really don't know when we have an 7 investigation or agent. There is just so much you 8 don't know. So the focus needs to be on the patient. 9 The other concern that has emerged for us 10 and in the cancer world specifically -- I really don't 11 know much about this in other settings -- is 12 increasingly frequent, the rush to approve drugs so 13 this concept of accelerated approval because we need 14 to save lives. And it is becoming our way of life. 15 So what happens is that yes, you develop 16 these research protocols. You develop primary 17 endpoints, secondary endpoints. And then when you are 18 looking in the interim analysis of data and then you 19 meet the secondary endpoint, data safety monitoring 20 boards are in a panic because we need to release the 21 data. We need to stop the trial because we met a 22 secondary endpoint. 68 1 I believe and we believe that we need to 2 be disciplined about this and that we need to conduct 3 ourselves in an ethical manner, of course, when we are 4 designing these trials and then have the discipline to 5 conduct the trials as planned. 6 There is a concern about the role of data 7 safety monitoring boards. It is a reasonable concern 8 to think about who are you trying to protect when you 9 are serving in a data safety monitoring board. Are 10 you trying to protect the patients that are enrolled 11 in the trial that you are looking at and/or are you 12 trying to protect future users of that intervention? 13 It is a dilemma, and it is a very 14 difficult point of course when you see issues of 15 safety that show up early on, absolutely you need to 16 be protecting the patients that are participating or 17 the participants in the trial that you are a part of. 18 But it is a dilemma. And it's not to give 19 answers quickly about this way or that way, but I 20 think we need to carefully look at that system because 21 we are approving drugs. We are getting drugs in the 22 market. We are given accelerated approval. And then 69 1 are very lax often on the post-marketing surveillance 2 of those drugs. 3 And so we find out that, in fact, yes, we 4 had some information, some signals of efficacy, oops, 5 but then there are issues of site safety, but by that 6 time it may be too late for too many people. 7 So there is plenty of room for 8 improvement. We strongly believe that consumers need 9 to be part of that discussion. And our approach 10 really is to educate consumers, give consumers the 11 tools to be participants, to be peers with the 12 community, and to really make our system of research 13 better and to protect participants in the process. 14 Thank you very much. 15 (Applause.) 16 CHAIRMAN PRENTICE: Thank you very much. 17 It's remarkable what your National Breast Cancer 18 Coalition has accomplished. 19 Would all three panelists please assemble 20 at the front table? 21 MEMBER ADAMS: Ernie, do we, by any 22 chance, have a copy of the CIRCARE recommendations? 70 1 They were not with our handout here. 2 CHAIRMAN PRENTICE: Again I would like to 3 thank all of you for your very informative 4 presentations. As the Chairman's prerogative, 5 everybody knows that I always get to ask the first few 6 questions. 7 I want to begin with a comment that takes 8 us back to 1995, when President Clinton's Advisory 9 Committee on Human Radiation Experiments issued their 10 report in 1995, which basically expressed concern 11 about the adequacy of human subject protection. 12 That was followed by the 1998 OIG report, 13 which implied that the system was in danger of 14 basically collapsing. And a lot of things happened 15 after 1998, including, as you know, the very tragic 16 death of Jesse Gelsinger as well as Ellen Roche at 17 Hopkins and a whole series of shutdowns. 18 Those of us in the IRB world saw a lot of 19 changes in the system. And I think we would all agree 20 that more changes need to be made, but I think many of 21 us that are in the IRB system think that there have 22 been significant improvements, which leads me to my 71 1 first question. And I would direct it, in particular, 2 to Paul Gelsinger but also to anybody else who would 3 like to comment. 4 Paul, in your comments, you indicate that 5 the current system for protecting human subjects in 6 research is ineffective. And, of course, we're 7 talking about the current system, 2005. 8 Then you go on to say that since no 9 meaningful improvements have been instituted, 10 investigators, sponsors, and research institutions 11 must prefer that the system remain the way that it is. 12 You obviously have been looking at the 13 evolution of our system, in particular, since 1999. 14 I wonder if you might clarify your position a little 15 bit further that you don't really think that there 16 have been any meaningful improvements. 17 MR. GELSINGER: Ernie, what I mean by that 18 is that the improvements that have been made have been 19 minor in relation to the size of the problem. 20 In gene therapy, they have created a 21 serious adverse event reporting system, which is fine 22 for gene therapy, but that has not carried over to the 72 1 rest of research. And gene therapy is only a very 2 minute part of all of research. So that is an 3 improvement, but in relation to the whole system, it's 4 not significant enough. 5 The improvement of the IRB system, a lot 6 of IRBs have upgraded themselves because of what 7 happened to Jesse, but there's no mandate behind that. 8 And a lot of institutions have not upgraded. They 9 don't have the funding for it. The resourcing isn't 10 there. And that needs to happen. 11 And there's no push behind any of this. 12 There's no legislation. There's no legislation for 13 the protection of human beings. We have it for 14 animals. And we have had that for a long time. And 15 those things need to happen. And it just hasn't been 16 happening. That's why I say it's ineffective the way 17 it is now. 18 CHAIRMAN PRENTICE: Okay. You make a 19 series of recommendations, which you didn't really 20 have an opportunity to talk about in any kind of 21 detail, but you indicated we would probably get to 22 them. 73 1 One is your view is that the OHRP, Office 2 of Human Research Protection, is basically 3 inadequately staffed to handle the volume of research 4 that requires oversight. And you cite the figures for 5 federal-wide assurances and the number of employees. 6 Have you looked at that in any more 7 detail? Would you like to comment on it? 8 MR. GELSINGER: I would like to defer to 9 Adil Shamoo to answer that. He has a lot more 10 background in this area. But my own experience in 11 dealing with OHRP -- you know, within a year of 12 Jesse's death, I started public speaking. 13 The first place I spoke at I had people 14 from the OHRP coming up to me and hugging me because 15 their funding had been increased fivefold to help them 16 do their job. 17 And it's still not enough. We need to 18 massively infuse money into the oversight of research 19 so that it's done ethically and that everyone gets to 20 take a good, hard look at everything that is being 21 done. We don't do that currently, and that is what 22 really needs to happen. 74 1 But I would like to defer to Adil because 2 he knows so much more about all of this than I do. So 3 if you could direct your question to him? 4 CHAIRMAN PRENTICE: Adil, would you please 5 come up? 6 DR. SHAMOO: I am Adil Shamoo from 7 CIRCARE. I think what Dr. Prentice is talking about, 8 really, and directing his attention and focus is in 9 those institutions he is familiar with; that is, Johns 10 Hopkins, University of Nebraska, and University of 11 Oklahoma, those institutions who got into trouble, 12 they are on the radar screen. 13 And if you look at the number of these 14 institutions compared to the overall, the latest 15 number I have heard is somewhere between 7,000 to 16 9,000 IRBs in this country. And we don't know how 17 many IRBs exist who only submit to the FDA, which does 18 not yet require registration. 19 Now, remember, just four years ago, there 20 was no registration for any IRB, how in the world you 21 could monitor a system. You don't even know where 22 they exist. 75 1 So if you look at -- let's take a number 2 of 7,000 IRBs, the one you're talking about -- and 3 they have done upgrading and have improved a couple of 4 hundred IRBs. I will give you even 500 IRBs. I'll 5 give you even 1,000 IRBs, 2,000 IRBs, 5,000 IRBs. You 6 still have 3-4 thousand IRBs. 7 You don't know a thing about them. 8 They're a mom and pop operation. They're all across 9 the country. And my experience with some of them, 10 they could do anything. And you wouldn't know what 11 kind of informed consent, what kind of approval. 12 So the system really has improved only in 13 a small percentage of those IRBs who are on the radar 14 screen. So to claim there is improvement, you have no 15 data and OHRP has no data to show me there is a 16 commensurate improvement where it's an effective 17 outcome of these IRBs since 1998, the date you 18 mentioned. 19 I have seen no published data indicating 20 that there is a better outcome in the protection of 21 human subjects. 22 CHAIRMAN PRENTICE: Okay. Thank you. 76 1 One correction. Oklahoma and Hopkins got 2 in trouble. Nebraska didn't. 3 (Laughter.) 4 DR. SHAMOO: I did not claim they got in 5 trouble. 6 CHAIRMAN PRENTICE: We were right in the 7 middle. 8 DR. SHAMOO: I said those who are on the 9 radar screen. And you are on the radar screen because 10 you are here chairing this Committee. 11 (Laughter.) 12 DR. SHAMOO: So you bring fame and 13 watchful eyes on you. 14 CHAIRMAN PRENTICE: I live in fear of an 15 OHRP site visit to my institution. 16 (Laughter.) 17 CHAIRMAN PRENTICE: I am going to ask one 18 last question. Then I'm going to open it up to the 19 rest of the panel. And this is for all three of you. 20 Paul, you make a recommendation. CIRCARE 21 makes a recommendation that 51 percent of IRB 22 membership should be local independent community 77 1 members. And, of course, we have heard those kinds of 2 recommendations before. 3 Running an IRB, one of the -- and I 4 certainly agree that we need a lot of community 5 involvement, but I just want to set the stage for your 6 responses. 7 One of the problems that we have on an IRB 8 is trying to get sufficient expertise to review the 9 protocols which are highly scientific. For example, 10 if you have a complex oncology protocol involving 11 peripheral stem call transplantation high-dose 12 chemotherapy, I'm very reluctant to assign that 13 particular protocol to, for example, a Bob Hauser, who 14 is a cardiologist. I really want to have at least one 15 oncologist. 16 Many IRBs are up to 23, 24 members now. 17 So if we had 51 percent of, let's say, a 24-member 18 IRB, you're talking about roughly 12 community 19 members. I would worry about how we would handle the 20 scientific aspects, the medical aspects of the review 21 with a membership that consists of independent 22 community members, who often don't have the scientific 78 1 expertise. So I would invite all three of you to 2 comment on that. 3 MR. GELSINGER: Since we proposed the 51 4 percent, I'll take the first shot at this. You always 5 ask for more than you know you are going to get. 6 (Laughter.) 7 MR. GELSINGER: We would really be happy 8 with a 25 percent representation on IRBs. I'm on 9 another board, Partnership for Human Research 10 Protection, which is an accrediting company. And we 11 had a consumer advisory group, which I am co-chair of. 12 Out of that came a recommendation, a 25 percent 13 representation on IRBs. So this isn't just CIRCARE 14 that feels this is necessary. 15 I agree with you that IRBs don't have the 16 expertise to review a lot of these cutting-edge 17 technologies. Even if it was all scientific, people 18 on the board itself -- you know, that should go out to 19 consultants to be able to interpret for the IRB. 20 And that's one of the issues that we have 21 at CIRCARE also is what is an IRB doing the scientific 22 review for in the first place? They're not qualified 79 1 in a lot of cases to do it. And that should be an 2 outside group doing that for the IRB. 3 The IRB really should be dedicated towards 4 the ethical review of research, the consent process, 5 those aspects of running clinical research, rather 6 than the technical review. 7 It's such a burden for them to carry all 8 of that. It is not fair to the system to put all of 9 that on one group. The Institute of Medicine in their 10 book, Responsible Research, which they issued in 2003, 11 gets into that and how to break down the system better 12 and divest some of this work into other groups to ease 13 the burden on IRBs. 14 We need a stronger community 15 representative. And I don't even think you have a 16 community representative on this Committee that you 17 have sitting here right now. And that's -- 18 MEMBER WEINER: Sorry. I am not chopped 19 liver. 20 MR. GELSINGER: Okay. Well, you are only 21 one of how many? And how effective is that? This is 22 supposed to be about human research protections. 80 1 Okay? You have one person that is representing the 2 human side on this. The rest of you are either the 3 business side of it, the government side of it. 4 You need more people that have actually 5 participated in research that have insight into that 6 experience in order to give you the proper feedback of 7 what it means to be a human research participant. And 8 I would just encourage that, you know, future 9 Committees have that representation. 10 Thank you. 11 DR. HINESTROSA: Well, as I mentioned, we 12 developed a set of training programs to really give 13 consumers the language of science and understand the 14 research progress, not to give them the latest in 15 breast cancer sciences, know what is going on and what 16 you should get or shouldn't get. 17 It is really to go give the foundations 18 that you can look and review a protocol, review a 19 research proposal, and really make sense of it and see 20 whether this is something that looks at its 21 limitations, its promises. 22 So I do believe that we are serving in the 81 1 breast cancer. We are working towards setting 2 consumer empowerment to precisely prepare consumers to 3 serve in those settings: IRBs, review committees, 4 peer review settings, data safety monitoring boards, 5 steering committees, and have meaningful participation 6 on equal footing with scientists on those committees. 7 I will say that I participated in the 8 pilot central IRB of the National Cancer Institute, 9 which was a very, very enlightening but also very good 10 experience for me. It was the very first and only IRB 11 service I have done. And I felt that it was like the 12 perfect IRB. 13 We have in that committee the 14 representatives of -- we have pharmacists. We have 15 surgeons, oncologists, general practice, 16 biostatisticians. I think they were consultants. I 17 don't think we had one serving. And we had about 20 18 to 25 percent consumer representation on that IRB. 19 Interesting things in that experience. 20 While the process was what I felt an IRB should be, 21 receiving the protocols on time, assigning -- there 22 was always a scientist and a consumer, who would core 82 1 review reviewers of the protocol. 2 The problem was, really, why are we doing 3 this trial? I kept asking the question, why are we 4 doing this trial? Is it necessary to spend the 5 resources on this. There is nothing terribly wrong 6 with it, not that you're putting people in much 7 danger, but why do we need to just because this drug 8 is available to be just trying on these people just to 9 see what it does. 10 So the major question was that. And I 11 think that is a relevant question to patient 12 protections. The type of research we're conducting 13 and putting their lives, the times, the resources of 14 our -- the scarce resources we have on really 15 important and meaningless research. 16 Another issue that was that I observed 17 firsthand was the pressure from the investigators' 18 community to approve this thing quickly. In the 19 community, the IRB is a hurdle. It is an obstacle. 20 It is a problem. You just can't do research because 21 the IRBs get in the way. 22 So we have a leading thought leader in the 83 1 cancer community because we rejected his protocol. He 2 came the next time. He said, "I'm not moving again 3 until you approve my protocol." He flew from -- I'm 4 not going to say where because you'll know who the 5 person is -- really to harass the IRB into approving 6 his protocol. So that is clearly a problem. 7 Interestingly, through all of that effort 8 and all of the work that was done -- and I think the 9 process was again what I believe the IRB should be. 10 I was talking with somebody. I went to an 11 IRB -- I don't -- know three years ago or so. I was 12 asking a researcher in the breast cancer community, a 13 clinician in the breast cancer community, about that 14 IRB and that process. 15 A colleague of his was a member of that. 16 He said, "You know, good as it was and what your 17 experience was, in all of these years, we have had 18 nine patients whose participation in the clinical 19 trials were impacted by the central IRB." So it was 20 this beautiful island of what it should be but had no 21 impact. 22 So I believe that it is really a wasted 84 1 effort into doing something the right way but, in 2 fact, it didn't have the implications because -- and 3 I don't know all the technicalities and the legal 4 issues for local IRBs. Local IRBs have to do their 5 own reviews. 6 So you had this layer up there with sort 7 of like the super team of players in an IRB, but at 8 the end, the local IRB had the responsibility. Things 9 had to be rereviewed there. And then people said, 10 "Well, it is a slow process. It really didn't help 11 us." 12 So I think those well-intentioned efforts 13 really need to have a reality check and real world 14 check so that they can really have the impact they 15 need to have. 16 So I think that it can be done. I think 17 that consumers can be -- the concern that they won't 18 have the expertise, we heard that when we insisted and 19 demanded that we have a seat at the table in the 20 research protocols. 21 Everyone was very concerned about who are 22 we to be doing that, but, in effect, we really have 85 1 transformed many, many minds, certainly through the 2 DOD Breast Cancer Research Program. And the 3 partnership between consumers and scientists in doing 4 this we believe has improved the research process. 5 CHAIRMAN PRENTICE: Thank you. 6 DR. HUFF: I don't have much to say about 7 IRBs. I don't have much experience with them. I 8 don't know anybody who is on one. And they have not 9 crossed my radar screen too much. They're sort of out 10 there. Maybe it's a bunch of men in black robes 11 sitting in a room somewhere just passing judgment. 12 It's a very odd thing. 13 But when I hear about them, it's either in 14 the context of, well, we're saying this is a terrible 15 study and they're saying, "But no, no. The IRB 16 approved it" as if that's all I need to hear. So I 17 don't think that's an endpoint for me in terms of 18 validating the quality of research. 19 Something you say is we see a lot of 20 studies for post-marketing of drugs that are just 21 designed to sort of produce information to sort of 22 flesh out the picture of a drug in the marketplace. 86 1 And you really have to wonder if that's an ethical use 2 of participation with human subjects to just sort of 3 reposition a product in the minds of prescribers. 4 That's all I'll say right now. Thanks. 5 CHAIRMAN PRENTICE: Felix? 6 MEMBER KHIN-MUANG-GYI: Thank you. 7 Paul, I appreciate your comments. Every 8 time I hear you speak, I do get moved because as a 9 parent of a child, I think it's hard for any of us to 10 fathom loss of a child in a setting such as this or 11 any setting but especially in a setting like this. So 12 thank you for taking the time to continue to remind 13 us. 14 I will say, though, in defense of the 15 statements that you made regarding some of the folks 16 around the Committee, you know, there are many of us 17 who have participated in research, including myself. 18 I think there are people who represent 19 that perspective in different ways, even though we may 20 not be in a professional setting of consumer 21 representative or consumer advocate in the way that 22 you might define it. 87 1 So I would ask you to be at least 2 appreciative of that position that we take in sitting 3 around this Committee because, as Dr. Prentice had 4 mentioned before, we had accepted the charge on this 5 Committee to make a difference and not let some of the 6 opportunities that had gone before us be squandered in 7 a way that people see that previous committees might 8 have done. There was lots of scholarly work that was 9 done, but in terms of practical output, I don't think 10 we see many of that. And I think that is what 11 everybody is saying. 12 I think that we also ought to remember 13 that just because we represent different sectors of 14 the research industry, that we don't have three heads. 15 I do represent an independent IRB, but if you take our 16 SACHRP members and staff, if you speak to any of them, 17 they will tell you that they are in business for one 18 thing and one thing only. And that is human subject 19 protection. 20 And if that permeates throughout the 21 industry or the company that people are in, then it 22 sort of puts the focus in the right place. We may not 88 1 be able to do all of the things in a timely manner 2 that we have suggested as well. So I would ask you to 3 just keep that in mind and work with us to help us get 4 to some meaningful outcomes. 5 As I hear the panelists speak, one of the 6 things that I'm concerned about is the different 7 positions that you take. You all make a statement 8 about IRBs needing to be a little bit more of a 9 gatekeeper. 10 But I wonder which gate we're supposed to 11 be keeping. There's a scientific gate that you want 12 us to approach. There's an informed consent gate, 13 resource allocation gate. I mean, there are lots of 14 gates. 15 And the evolution of the IRB has been to 16 layer more work onto the IRB system, as opposed to 17 saying, "What can we all take off? If we're going to 18 put this on the IRB, what can we take off?" 19 And so in your observations and 20 recommendations, I would ask you to keep that in mind 21 as well to help us to understand what it is that we 22 need to reallocate appropriately because this is, 89 1 after all, a research team and an enterprise that is 2 made up of more than just IRBs. There are 3 investigators. Subjects have to be involved as well 4 and informed in a way that helps the system work a 5 little bit better. 6 Having said that, my charge on this 7 Committee is to serve as a co-chair of a subcommittee 8 looking at Subpart A. One of the things that we're 9 going to look at is the informed consent section. 10 And I wonder if you might give us some 11 guidance. All three of you have spoken to the issue 12 of informed consent. And I wonder if you might give 13 us some guidance in terms of what you would like to 14 see happen or come about from that particular group's 15 activities. 16 MR. GELSINGER: I have only been through 17 the informed consent process once, and that was with 18 my son, when he went and was tested to see if he could 19 participate in that clinical trial. He went through 20 not only the consent for that testing but the consent 21 for the entire process he was going to go through. 22 After his death, it started coming out the 90 1 ways that that process had failed. And that is where 2 this Committee needs to put its focus. You know, 3 there is a consent form that is put out there. The 4 IRB reviews a consent that goes along with the 5 protocol that's going to be conducted. 6 The focus I really think should be that 7 that consent process that's going to be undertaken for 8 that protocol actually reflects what is going on in 9 the protocol. That's a difficult problem because you 10 are so reliant upon the investigator to give you all 11 of the facts that are going on in the clinical trial. 12 And, yet, it's also very difficult for him to insert 13 all of that in the consent process. 14 There has to be a very great transparency 15 and a lot of expertise involved in analyzing the 16 actual protocol, the preclinical work that has been 17 done in making sure that whatever a human subject 18 needs to know is incorporated in that consent form so 19 that they see and understand that. 20 We didn't get that. And this was overseen 21 by the IRB at Penn. Okay? They did a very inadequate 22 job of making sure that the consent form was accurate, 91 1 that it had all the information it did. 2 There was information removed from the 3 consent form and then it was approved by the IRB 4 regarding the deaths of animals in the preclinical 5 work. We didn't have any knowledge of that. 6 MEMBER KHIN-MUANG-GYI: Would that have 7 changed your mind? 8 MR. GELSINGER: Well, that in conjunction 9 with the toxicity in human beings that are already 10 occurred at one-tenth the dose that Jesse got, it 11 would have made a big difference in my decision for 12 him to participate. 13 He didn't meed to be there. He was on a 14 drug that had his condition under very good control. 15 He only wanted to help others. But this was an 16 invasive technology, cutting-edge invasive technology, 17 that had serious side effects that we weren't aware 18 of. And he didn't need to be there. 19 Now, it's the IRB's responsibility to make 20 sure that that information is given to the research 21 subject. And we didn't get that. So that is really 22 where the focus needs to be, that what that consent 92 1 form is actually what is going on in the clinical 2 trial, and update that ongoing. And that didn't 3 happen either. So it was just a very inadequate 4 process that occurred for us. 5 Now, Penn has upgraded their IRB system 6 fivefold. I mean, they've infused a lot more money. 7 There are people who have come and thanked me at 8 meetings, people that are now on Penn's IRB. Because 9 of what happened to Jesse, they now have the 10 resourcing to do the job that they need to do. 11 And that's what needs to happen in the IRB 12 system. We just need more focus there to make sure 13 that what is presented in the consent is actually what 14 is going on in the protocol. 15 DR. HINESTROSA: Well, I think, first I am 16 going to repeat myself a little, but I think that 17 there is a problem when the research community sees 18 the IRB system as a problem, as a burden, as 19 something. And so if you see it as an obstacle, find 20 ways to get around it. And so I think where you're 21 talking about information not being put on consent 22 forms, probably it's a result of that. 93 1 Again, I have not participated in 2 research, in clinical trials myself. When I wanted to 3 do it the second time I had breast cancer, I wasn't 4 eligible because I already had cancer once. So I 5 could not participate. 6 My experience has been through serving an 7 IRB. And, as I have said to you, I have thought that 8 that was a very really meaningful and good experience, 9 but I also became very aware that that was unreal and 10 realistic because we really had the luxury of the 11 expertise that was there. 12 We had the luxury of time to review a 13 number of protocols. For each meeting we had maybe -- 14 I don't know -- five or six or maybe ten. I 15 understand that IRBs may have to review 50 protocols 16 at one meeting. And so what kind of analysis can you 17 do? How deeply can you go into your studying of each 18 protocol to sort of fully understand what can be done? 19 So it concerns me greatly that, even 20 though we have talked and there have been initiatives 21 to test whether a central IRB is a good idea and 22 whether that is something that could help this 94 1 fragmented system and this burdened system, it 2 concerns me greatly that we haven't yet really fully 3 tested that concept to see whether it really works. 4 I do believe that it is very important 5 that IRBs not only focus on the informed consent form 6 because you can only have a good informed consent form 7 if you really, truly understand what the research is 8 about, what the limitations of the research are, what 9 the problems, potential problems, of the research are. 10 So it is absolutely relevant to the work 11 of an IRB to have a discussion on the scientific 12 merits of the research. I do remember that when we 13 started that IRB and I was at the beginning of that 14 pilot, people were saying, like "Why are we 15 reanalyzing the science?" We believe that is very 16 important. 17 I mean, it was ethically relevant to 18 engage in this and to people at the Committee who were 19 experts saying, "Well, there is this study here that 20 is not presented in this protocol. What happened with 21 this research?" It should be there. There should be 22 information to the potential participant about these 95 1 other studies that don't show up here in the consent 2 document. 3 So, again, I really insist. And we have 4 seen the impact of having informed consumers 5 participating in the process, but I think it's also 6 important that we really try to find a better system 7 that -- I know you're working on that -- to see how we 8 can create economies of scale in terms of the 9 expertise that is required to be looking after six 10 protocols. 11 DR. HUFF: When we first started looking 12 at informed consent forms 15 years ago, they were sort 13 of just cover your butt forms. It had gotten better. 14 I want to say that we should not think about them as 15 forms. It should be a process. 16 And consenting is a process. It is an 17 engagement between two people or more people, 18 educational process. It's coming to an understanding. 19 It's an experience. 20 Most of what I see I think are 21 pharmaceutical-sponsored studies. And those informed 22 consents are written by people who -- I mean, they 96 1 have deep pockets. So they hire people to do this. 2 They've gotten very good at it. We often see them 3 before they go to IRBs and comment on it and have some 4 input into it. 5 But just because I understand it doesn't 6 mean that the individual that's going to be presented 7 with this understands it. So that process has to 8 continue. And in reality, it's not so much what's in 9 the form. It may be the interchange between the study 10 nurse and the person. 11 I want to go international settings for a 12 while because this is where I am hearing the horror 13 stories now. That study nurse may be contracted 14 because they have expertise in local languages. And 15 they don't have the training to -- and they have 16 incentives to enroll people. So they may say, "Oh, 17 it's going to be good for you to sign up." I mean, 18 that's the extent of it. 19 So what is in the form is just the 20 beginning. And developing the form itself can be a 21 long learning experience. In the developing of trials 22 for microbicides in South Africa, it was an ongoing 97 1 process that has gone on for years in working on the 2 informed consent process, which includes videos and 3 scripts as well as the form that you sign. 4 So let's get away from forms. I like your 5 idea of taking informed out of it. It's the consent 6 because you don't know what is received at the end of 7 the day when someone signs. 8 DR. HINESTROSA: It is not my idea. IOM 9 actually came up with that idea, which is -- I guess 10 just one thing, if I may, which is that my experience 11 with my central IRB, at the beginning, you have to 12 understand you give the informed consent to the 13 consumers. So we do our thing here, and you give the 14 thing. And you can see if we should use -- I don't 15 know -- lay terms for headache or whatever. But it is 16 not about that. 17 Of course, you want this information to be 18 understandable. It is fourth grade or fifth grade 19 language, but that is not the point. The point is 20 what information are you trying to translate into 21 understandable terms. That really needs to be there. 22 And that is an issue. 98 1 The other piece to this that I think is 2 important, although may not seem directly related to 3 the work of this Committee, is, as someone mentioned, 4 the registry of clinical trials and registry in making 5 sure that the outcomes of research are publicized and 6 disclosed because, as we know, only positive results 7 are the ones that tend to be published. 8 And so we don't know about the negative 9 resource. We don't know about the bad stories because 10 those are kept hidden or just in the minds of the 11 people who conducted the research. 12 And so if we have registration of clinical 13 trials and then discussion of outcomes of all 14 registered trials and if we complied with that, there 15 will be information for all potential participants on 16 what has gone on with this research, the good, the 17 bad, the ugly, and the pretty about this. 18 So all of that is essentially to say there 19 are several parts of the system that need to be 20 working at the same time but that access to 21 information is essential, essential to consumers so 22 that, again, we can really truly be knowledgeable, at 99 1 least, of what is going on. 2 CHAIRMAN PRENTICE: Okay. Thank you. It 3 has been a very interesting dialogue. 4 We have a problem. It's break time. I 5 would like to cut the break back by five minutes. I 6 have five individuals who are on my list who have 7 asked to ask questions. Which honorable SACHRP member 8 would like to yield to which honorable SACHRP member? 9 (Laughter.) 10 CHAIRMAN PRENTICE: People on the list are 11 Tom, Nancy, Celia, Bob, and Susan. We have two. If 12 you can keep your questions succinct and the answers 13 brief, we can probably get two more in before the 14 break. 15 (Laughter.) 16 CHAIRMAN PRENTICE: And then we'll have an 17 opportunity this afternoon to maybe continue. So who 18 is up? 19 MEMBER JONES: I just have a quick 20 question. 21 CHAIRMAN PRENTICE: Tom has yielded. 22 You're number three on the list. 100 1 MEMBER JONES: Okay. 2 CHAIRMAN PRENTICE: Okay. Go ahead. 3 MEMBER JONES: Well, my quick question is 4 this. I know that, especially in the groups you have, 5 you have been effective in getting funds for research. 6 Have you also advocated for funds to do this human 7 protection? I mean, if it is a priority, what 8 percentage of the research funds would you be willing 9 to put into that? 10 MR. GELSINGER: We don't get any funds 11 from anybody, and that is a problem for us that there 12 is no funding for groups like us to advocate for 13 better protections for human research protections. I 14 mean, we have to go out and generate those funds 15 ourselves. 16 MEMBER JONES: I think I was more 17 specifically talking to the people who were funding 18 research, like NIH or Cancer Institute or different -- 19 DR. HINESTROSA: Well, I can speak about 20 the DOD Breast Cancer Research Program because I have 21 been a part of it. I am still a part of it. 22 The program announcement, the group that 101 1 designs the mechanisms for research, we have never 2 directed research in one or another direction. There 3 has been great pressure to say, "You should be. Why 4 don't you this here, put in qualified applications 5 for" -- I don't know -- biomarker research or 6 monoclonal antibodies or whatever or stem cells or 7 whatever? We have never done that. 8 We say that we really want to bring this 9 mechanism to the community, get the community to give 10 us their innovative ideas where they're ready to do -- 11 they're bold new steps because we reward the 12 innovation. 13 So we mentioned areas, general areas of 14 research. And we talk about prevention, treatment of 15 care. But we also have health services research, 16 economics. We are trying to bring people from the 17 nontraditional sciences in sort of breast cancer 18 research mathematics, physics. 19 Unfortunately, what we get is the 20 traditional. I don't mean unfortunately 21 unfortunately, but we don't get enough proposals in 22 health services research in economics and all of those 102 1 areas. 2 If people took the time to read the 3 program announcement, they would know that we are 4 interested in that type of research and that those 5 under-served areas of research will be looked at with 6 great interest. 7 So I guess perhaps we're not doing a good 8 job ourselves of publicizing that. Just one thing I 9 would say is that we don't get any money from that. 10 I mean, it is money that is there for the community, 11 but it does not come to the National Breast Cancer 12 Coalition. It comes to the DOD. 13 CHAIRMAN PRENTICE: Okay. Celia, Bob, 14 Susan, one more. 15 DR. HAUSER: I would like to talk a little 16 bit about the money. There was a lot of money 17 involved in the trial, Mr. Gelsinger, involving your 18 son. There were conflicts of interest involving the 19 investigator. There was significant ownership by the 20 institution in the company that was eventually sold I 21 think for quite a bit of money. 22 How do you feel about investigator 103 1 conflict of interest? Very specifically, what level 2 of participation should an investigator have in the 3 financial outcome of a study? Should it be none? 4 Should it be some limit or perhaps unlimited? Can you 5 give us some sense of that? 6 And also how did you feel when you learned 7 that the University of Pennsylvania actually owned 8 stock in the company that was involved? 9 MR. GELSINGER: When I read the consent 10 form, there was a one-sentence paragraph at the very 11 end that stated that Dr. Wilson, Genovo, and the 12 University of Pennsylvania had a vested interest in 13 the outcome of this clinical trial. 14 I'm a businessman. I had my own business 15 at the time. I always had a vested interest in 16 whatever I did. But having gone through this whole 17 experience and the connections, all the little strings 18 that are attached to that financial connection, these 19 guys should have absolutely no financial interest in 20 the work they are doing. And if they do and they 21 still want to do the work, they should have to sell 22 that interest before they do their work. 104 1 It taints everything. It puts blinders 2 up. They're not going to be able to see everything 3 they need to be able to see because of that financial 4 interest. 5 You know, these three docs that did this, 6 I've seen them as victims also, victims of the system. 7 This goes back to the Bayh-Dole Act that tried to 8 promote pushing products from academia out into 9 industry by creating entrepreneurship. They never 10 addressed the conflict of interest issues that went 11 along with that. 12 And it's a big problem. It's one that's 13 enmeshed in our whole society now. The whole academic 14 society is full of it. These guys should not have an 15 interest in what they're studying. If they do, they 16 should recuse themselves from overseeing the work and 17 give it to somebody else. 18 If they're the only expert to do it, then 19 they need to sell their ownership rights if they want 20 to do the work. That's the only real solution to 21 that. 22 DR. HAUSER: What about the institution? 105 1 MR. GELSINGER: The institution, if it 2 wants to have a vested interest, institutions need an 3 income stream. I mean, the researchers themselves are 4 paid well enough, but I understand how the 5 institutions need that income stream and ownership 6 rights and everything. 7 But then if they're going to do that, then 8 their IRB can't be the one overseeing the study. They 9 need to get that out of their hands and make sure that 10 the firewalls are in place, make it totally ethical 11 that the oversight on this thing has got their hands 12 off of it. 13 And they shouldn't even be dealing with 14 the conflict of interest issues, then, either. They 15 should be farming that out. And the system is not set 16 up that way now. So that would take a lot of work to 17 undo that and put up something that would work in its 18 place. 19 DR. HUFF: I would just quickly say the 20 pharmaceutical industry is very adept at enmeshing 21 almost anyone with any talent or influence into some 22 kind of a relationship. In HIV, this is especially 106 1 true. 2 In the end, though, I think it's 3 transparency and willingness to have some kind of 4 critical -- someone willing to speak out, which 5 doctors maybe aren't so often as people like I am. 6 CHAIRMAN PRENTICE: Okay. Susan, comment? 7 MEMBER WEINER: I think what we have heard 8 this morning is change that has come about as the 9 result of informed activism on the part of disease 10 groups. 11 The question about human research 12 protections is not a question related specifically to 13 a human disease group. It relates to all people who 14 participate in clinical trials in human research. 15 I think that the question about money is 16 the key issue here because it's not clear what the 17 driving force could be for the kind of reform in 18 research protections that would be like the kind of 19 reform that we saw in breast cancer research and HIV 20 research for the topic of human research participation 21 in general. 22 CHAIRMAN PRENTICE: Okay. Thank you. 107 1 We're going to take a ten-minute break. 2 And we're going to reconvene for the next panel. 3 Thank you very much. We appreciate it. 4 (Applause.) 5 (Whereupon, the foregoing matter went off 6 the record at 10:40 a.m. and went back on the record 7 at 10:56 a.m.) 8 CHAIRMAN PRENTICE: We are going to get 9 started again. We're going to cut into our lunch hour 10 probably in about 10-12 minutes. Obviously these 11 panels are very interesting and we could really go on 12 for days, but, unfrotuantely, we have a very tight 13 time schedule. 14 So I would like to invite the first 15 speaker to come up to the front table. And while she 16 does so, I will intoruce her as Dr. Wanda Jones, who 17 is the Deputy Assistant Secretary for Health, 18 specifically Women's Health, in HHS. 19 And she has focused her efforts on 20 elminating health disaprities for women through a 21 variety of programs and initiatives, including the 22 National Centers of Excellence in Women's Health, the 108 1 National Community Centers of Excellence in Women's 2 Health, the National Women's Health Information 3 Center. 4 So clearly she has a long involvement in 5 women's health issues. I will not go through the 6 netire bio, but, needless to say, we are deligthed 7 that she has agreed to come and speak with us today. 8 The format, as you know, is the same as 9 the last panel. We will hold all questions until the 10 end of the presentations. And please try to keep the 11 presentations down to about 15 minutes, which will 12 allow adequate time for questions. 13 Welcome, Dr. Jones. 14 DR. W. JONES: Thank you, Dr. Prentice, 15 and members of the Committee. 16 PANEL 2: PERSPECTIVES OF RESEARCH SUBJECT 17 REPRESENTATIVES AND ADVOCATES CONTINUED 18 DR. W. JONES: I'm grateful for the 19 invitation to speak to you today and, you know, have 20 to say I was a little bit daunted by the invitation at 21 first, but after talking to some folks and giving it 22 a bit of thought, I said, "Okay. This is something I 109 1 can do." So here I am. Enough explanation. 2 It has occurred to me in listening to the 3 discussion this morning that every day, day in and day 4 out, women are using medicines or taking treatments 5 that have never really been tested among them. This 6 is true for people of color. It's true for older 7 people. It's true of people with disabilities. Think 8 of any other of a variety of groups that historically 9 have not been completely represented, if at all, in 10 the research, whether it is funded by the federal 11 government, whther it is funded by pharmaceutical 12 companies, no matter the sources. 13 And I guess we could look and say, "Well, 14 the good news is you look at how we have extended life 15 expectancy." We're not dropping like flies. 16 You know, the better news is that the 17 rules have changed so that in this Twenty-First 18 Century and, you know, frankly, started changing 20 19 years ago. But in this Twenty-First Century, we are 20 facing opportunities to redress some of those wrongs 21 that had been committed, required in federally funded 22 research to include women and minorities in the study 110 1 populations, strongly encouraged by FDA. I don't 2 think it's yet at the requirement level. 3 The bad news, though, is that the legacy 4 of all of those years of exclusion, some people have 5 been hurt. Some have even died using drugs, using 6 treatments that were completely approved and 7 prescribed by providers or used by patients or 8 consumers in good faith. But no one had a clue that 9 there might be a problem for particular populations. 10 So if I had to describe where we have 11 been, where we have come, and where we are going, I 12 think of a sector of the economy that seems to do 13 things very well and to respond very quickly and, of 14 course, is driven by much different motives than is 15 science or medicine. But that would be the retail, 16 particularly for women, perhaps the clothing industry. 17 Not too long ago, items would have one 18 size fits all on them. And then as our waistlines all 19 got a bit bigger and Americans grew quite a bit 20 larger, it became "One size fits most." 21 But the reality is what we know today and 22 as we look forward, one size fits one size. Now, that 111 1 doesn't mean we're going to move toward clinical 2 trials of one. That's not going to make anybody 3 happy. 4 But we've got statistical tools. We have 5 got research methods and designs that allow us to 6 include diverse populations of women and men to fully 7 understand some of the problems at all phases, Phases 8 1, 2, and 3, and then follow-up phases of drug trials, 9 of treatment and intervention trials. So there really 10 should be no more excuses. 11 The problem of not including women in 12 research actually represents more risk than does 13 inclusion because, as I've already described, once a 14 drug or treatment is approved or widely adopted, then 15 women who weren't tested are widely exposed, people 16 who were not part of the population widely exposed. 17 Among women, some of these women may be 18 pregnant. They may get pregnant. Some of the men may 19 not even fully understand that there could be a 20 reproductive effect to the drug or the treatment that 21 they have engaged in because it wasn't part of the 22 original study. But once you ramp up exposure, you're 112 1 going to see more and more adverse events. 2 Now, the history, sadly, for women in 3 research has been pretty poor. You know, as recently 4 as 50 years ago, beliefs about women's needs to be 5 included in anything that didn't affect the 6 reproductive system were pretty spotty. 7 In fact, even in reproductive research, 8 the conduct of research on contraception that was 9 conducted entirely without consent in Texas, in Puerto 10 Rico, among Latino populations, among low-income 11 populations is a record that is as despicable as any 12 other horrible research experience of populations not 13 given the appropriate consent for which we all 14 acknowledge Tuskegee as the lion in among all of those 15 horrible experiences and perpetrations to vulnerable 16 populations. 17 Even today, men are far more likely to be 18 invited to participate, to have opportunities to 19 participate in non-reproductive research than are 20 women. There are some reasons that are perfectly 21 legitimate, but there are some that are still, if you 22 will, vestiges of old thinking. 113 1 Well, historically some of the reasons for 2 women's exclusion -- because I never remember lists 3 anymore, I wrote this down -- study populations, less 4 homogenous, are harder to analyze. It's not just for 5 women. Mix up your population any way you choose, and 6 you could say that. Studies are more expensive 7 because they require more subjects. Okay. 8 Is it important to know whether those 9 other subjects are going to have a benefit or would 10 potentially use this product? So that one hardly 11 carries water any more. 12 Women are harder to recruit. I like that 13 one. I'll come back to that one in a little bit. 14 Here's another great one. Women's hormonal states, 15 their cycles, pregnancy hormones. They might be using 16 oral contraceptives. My God, they could be menopausal 17 or taking hormone therapy. These things could confuse 18 our research results. 19 I guess men don't have hormones -- 20 (Laughter.) 21 DR. W. JONES: -- or at least men's 22 hormones don't cycle quite the same way. You still 114 1 have circadian rhythms. You still have other hormonal 2 phenomena that men experience, but somehow women's are 3 much more challenging. 4 Women report more drug side effects. 5 Well, this comes from the hysteria that women have 6 been so long accused of in that our uterus controls 7 everything anyway. 8 (Laughter.) 9 DR. W. JONES: You know that the Greek 10 word for is hystero. And hysteria, hysterectomy, all 11 of those words are related, still hanging up there for 12 some folks. 13 And, finally -- and this one we don't take 14 lightly -- is the potential for exposure of a fetus or 15 the potential reproductive effect of a drug or a 16 treatment later on should a woman choose to become 17 pregnant. So all of those have been issues for 18 recruiting women into trials. 19 But it's more important now than ever that 20 this is changing, that NIH's guidelines for inclusion 21 are taken quite seriously for funding. In 2001, the 22 Institute of Medicine actually declared that sex is an 115 1 important marker of individual variability, that some 2 of that variability occurs in utero but manifests 3 later in life. 4 They recognize that inclusion of women is 5 not always feasible or appropriate, but sex, being 6 male or female, is an important basic human variable 7 that should be considered when designing, analyzing, 8 and reporting findings from studies in all areas and 9 at all levels of biomedical research. They went so 10 far as to acknowledge that some of the vaunted cell 11 lines in which research is commonly conducted actually 12 have their human origins, even their animal origins, 13 in either a male or a female of the species of origin. 14 And even though those cells may have 15 existed in culture or co-culture for many, many 16 generations, they're genotypically still male or 17 female. And so is it possible that even if you're 18 looking at cellular research, there could well be an 19 effect of sex? It's important to begin to examine 20 these issues. 21 One problem we have seen in inclusion of 22 women is actually the reporting of results, inclusion 116 1 of minorities as well. You know, you will see all 2 kinds of elegant studies reported. And in the 3 methods, they'll say, you know, "Women constituted X 4 percent of the study" or they'll spec out how many 5 people of color they had in their study. And then 6 when you get down to, well, what were the results, you 7 can't find anything in the tables. 8 Primary and secondary papers out of many 9 of our studies don't report results by sex or if they 10 report by sex, they don't report into the dimension of 11 race, ethnicity, or perhaps age or some other 12 dimensions that might be important. 13 More importantly, what impact does this 14 have on our evidence and our evidence-based medicine 15 that even the Agency for Healthcare Research and 16 Quality has acknowledged continues to be a problem. 17 I took a look at the 2004 studies that 18 were summarized on our National Women's Health 19 Information Center Web site. That Web site gets 20 between three and five million user sessions monthly. 21 There are a lot of consumer as well as 22 health professional media and other users of that Web 117 1 site, but in 2004 alone, there were about 2,000 major 2 medical findings that were posted. 3 When I looked more closely at 315 articles 4 posted between July and September, 63 of them covered 5 topics that should have addressed gender differences 6 or similarities because the topics were not unique to 7 either men or women, but only 17 of those 315 reports 8 actually addressed whether or not men and women were 9 included, whether there were any sex or gender 10 differences. 11 And then among the remainder of those 63, 12 over half failed to describe their studies 13 participants beyond "adults" or "patients." And, yet, 14 most of those studies were of sufficient size and 15 design that they should have been able to report even 16 rudimentary findings, but they didn't. 17 Single gender study populations 18 characterized 17 of those 63 studies. They talked 19 about things like the uri-genital tract, pregnancy, 20 breast-related studies. I'm sorry. I excluded 21 studies that met those criteria. 22 And then male-only studies, including male 118 1 rat-only studies, comprised 12. The study numbers are 2 small, but the male-only studies were more likely to 3 report that their results generalized to "people" or 4 "adults" or "patients"; whereas, the studies that were 5 clearly female-only and excluding reproductive-type 6 topics tended to say women. It didn't generalize to 7 men. So there's clearly something broken, not just on 8 inclusion and meaningful inclusion but on meaningful 9 reporting of results and understanding what our 10 science is telling us. 11 The Agency for Healthcare Research and 12 Quality conducted a review of coronary heart disease 13 studies a couple of years ago. And they update 14 periodically how much progress has been made. 15 You know, just to summarize the results -- 16 I see Dr. Chesley is over there. So I've got to be 17 careful. They found no data in women to address 13 18 subtopic questions important to coronary heart 19 disease. 20 Out of 40-some subtopic questions they 21 were asking, no data in women for almost a third of 22 those questions, weak data to address 15, fair data 119 1 for 8, good data for 6. And no evidence addressing 2 differences in the accuracy of diagnostic tests, 3 strength of risk factors, effects of treatment, and 4 prognostic values of markers for ischemia in women of 5 different races or ethnicity. 6 The only evidence regarding differences by 7 ethnicity suggests that African American women may 8 benefit more from treatment of hypertension than white 9 women. 10 We should know more about these health 11 problems. Heart disease is the number one killer of 12 women, just as it is for men. We should know more 13 than we do. 14 Part of AHRQ's approach is to try to get 15 the evidence that is not published. And, yet, 16 investigators either didn't have it or wouldn't 17 provide it. So that, too, is problematic. 18 They looked at several particular issues, 19 treatment and diagnosis, selected topics that they 20 reviewed. Eighty-two studies included women but 21 didn't stratify the data by sex. They got data from 22 only 19 studies, 23 percent of those studies to enable 120 1 them to look and see whether, in fact, there were any 2 sex or gender differences. 3 So that, too, is part of the responsible 4 conduct of research, is what's done with the results, 5 how the analyses are done and helping all of us 6 benefit from the investments we made in research. 7 Let me just step back to the issues in 8 recruitment retention of women because we have been 9 labeled difficult, non-compliant, hard to reach. 10 We've heard all those things. 11 Just a few issues that are themes when I 12 chat with women about what opportunities they have for 13 participating in research trials. One is relevance. 14 What is the subject under study? Who is the contact? 15 Who is the interaction between me, the study 16 participant, and the investigating team? Who is going 17 to stay in touch with me? What will I get out of it? 18 How is it meaningful for me or my family? 19 What about the convenience, the location, 20 the hours? You can report here between the hours of 21 9:00 and 5:00 Monday through Friday. What about child 22 care? It's no small issue. Overall support, who can 121 1 answer my questions for me? Can I think about this a 2 while, take this home, talk with my family? What 3 level of involvement do I have? 4 And the involvement issue, I mean, the 5 example that Carolina Hinestrosa shared with you about 6 their Project Lead and the similar effort underway in 7 the women heart disease survivor community to train 8 women about the science of medicine and clinical 9 trials is significant and is making strides every day. 10 But those are the only two examples I can think of 11 where that sort of thing is being done. 12 Transportation to the site. You know, it 13 deals obviously with the location and convenience, but 14 what about the hassle factor? If I'm a young, 15 reproductive age woman, do I have to change my method 16 of contraception? Do I have to use two methods of 17 contraception? What if I'm on hormone therapy or what 18 if I have another condition? 19 You know, often those are reasons for 20 exclusion from trials. And even postmenopausal women 21 had been considered historically not worthy of much 22 study because at that point, they must be just like 122 1 men anyway. You know, there are significant issues 2 for women postmenopausally that deserve a look. 3 How many of these factors apply to men? 4 A significant number of them. I'm not dissing the men 5 here at all. But to men's defense, how often are men 6 even counseled to use a condom because we don't know 7 what effect this drug might have on your potential 8 children. And how much, how often is that sort of an 9 issue a barrier for men? Are men really being done a 10 disservice in the ways in which research is conducted? 11 Let me drill down just once more and just 12 share with you just from personal insights. I've been 13 a participant in about five clinical trials since I 14 have been here in Washington since 1998. I've sort of 15 lost track. A couple of them have been drug trials. 16 Some are long-term observational trials. 17 I was just sitting there thinking about it 18 this morning. The consent has ranged from very 19 cursory, very legalistic, even for me with a college 20 and graduate degrees and all my years in federal 21 government. And I can read bureaucratese pretty well. 22 But some of these forms are so incredibly 123 1 obtuse. And I'm expected to simply read and sign it. 2 Asking questions? Not encouraged. You know, if 3 that's the way the consent process is, it's not so 4 good. 5 On the complete opposite, though, I've had 6 this completely engaging, fully open, and interactive 7 consent process and have been given a copy of what I 8 signed that has had like a 24-hour number to call if 9 I had any questions. Holy cow. 10 Isn't that the way it really should be? 11 I mean, I'd sign up for a whole lot more studies if I 12 had time and if I thought that's the way consent was 13 always done. 14 Convenience. And it's a huge factor for 15 me. I mean, I can take time off from work. I don't 16 get penalized. I've got leave I'll never use if I 17 live to be 100. 18 (Laughter.) 19 DR. W. JONES: But, you know, when I have 20 to be somewhere to pick up a drug only at a certain 21 time, you know, it's a little aggravating for me, too. 22 You know, why isn't there somebody there able to 124 1 dispense that when I can get there? And you're going 2 to call me non-compliant? I don't think so. 3 And then the hand-holding. In some 4 trials, it's been a wonderful interaction between 5 staff and the participant, you know, any questions. 6 Can I get you this? How can I help you, you know? In 7 other places, I feel like I am nothing but a bother, 8 just, you know, when you're done, you're out of here. 9 So those have been my experiences as a white woman 10 with a graduate degree interacting with a system I 11 know probably too well. 12 And I just think, "My God. Change any one 13 of those characteristics. And it changes the balance 14 of power. It probably changes the outcome of the 15 research. It certainly mans that subjects may 16 disappear, you know, never to fully complete whatever 17 the trial is." These are not all necessarily human 18 research issues. And, yet, they tie in so intimately 19 with the issues of human research protections. 20 So I thank you for the opportunity to chat 21 with you today and look forward to the questions 22 afterward. Thank you very much. 125 1 (Applause.) 2 CHAIRMAN PRENTICE: Thank you very much, 3 Dr. Jones. We really appreciate your comments. 4 I would like to now call Linda Wachtel, 5 who is the parent of a child diagnosed at 19 months 6 old with a brain stem tumor, which was diagnosed in 7 1987. And then treatment began in '89 with surgery, 8 chemotherapy, following reoccurrence, another 9 reoccurrence in 1994. But Tory has been free of any 10 tumor activity since 1995, but he is challenged by 11 medical issues and disabilities secondary to having a 12 brain tumor. 13 I'm sure that Linda is delighted that he 14 has just completed his first year of college and looks 15 forward to returning for his second year this fall. 16 Linda is a board member of the Children's 17 Brain Tumor Foundation. Thank you, Linda, for 18 agreeing to come here and talk to us. We look forward 19 to your comments. 20 MS. WACHTEL: Thank you for including me 21 as a parent in today's presentation. And I hope that 22 our story will prove meaningful for everyone in 126 1 representing the scope of this topic. 2 As you just heard, our story began in 3 1987, when our healthy 18-month-old son Tory suddenly 4 developed symptoms that initially appeared to be a 5 stomach virus. Over the course of the month, the 6 range of symptoms increased. However, many were vague 7 and transient. 8 After clear skepticism and direct comments 9 about anxious parents from the pediatric neurologist 10 we had been referred to, a CAT scan was finally 11 ordered. We were told this was just so we could sleep 12 at night and move on. 13 After having been offered a seat at the 14 CAT scan monitor, I watched until I was abruptly 15 brought to a private office, at which point Tory was 16 diagnosed with a very large tumor located in his brain 17 stem. 18 We were told that due to the precarious 19 location of this tumor, it might not be operable. We 20 were fortunate to quickly be referred to the 21 neurosurgeon who had recently pioneered surgery to 22 remove tumors from the brain stem. He had performed 127 1 no more than 30 of these surgeries at that time. 2 We were told there were many serious 3 risks, but clearly we had no choice. Surgery was 4 immediately scheduled. Nothing could have prepared us 5 for the journey we would begin or the changes that 6 Tory would go through. 7 Following surgery, our neurosurgeon, Dr. 8 Epstein, believed the tumor to be a low-grade 9 astrocytoma, but this needed to be confirmed by the 10 pathology report. 11 However, when the pathology report came 12 back, we were told by the neuro-oncologist that Tory's 13 tumor was, in fact, a high-grade malignancy and that 14 he would die from this tumor. 15 In the days that followed, recommendations 16 for chemotherapy protocols were presented to us. We 17 were told that treatment needed to begin immediately 18 or we would be putting him at great risk. 19 Two chemotherapy protocols were presented 20 to us. The first was a 3-drug protocol in which 20 21 percent of children had positive results. In the 22 following words, the neuro-oncologist explained, 128 1 "There is also a new protocol for an eight-drug 2 chemotherapy. You are intelligent parents. And any 3 intelligent parent would know that if 3 drugs helps 20 4 percent of the kids, then by increasing to 8 drugs, 5 the treatment will work that much better." We were 6 told that we would live most of the next 18 months in 7 the hospital. 8 It didn't seem like there was much room 9 for conversation and discussion. And given the sense 10 of urgency, it didn't even seem like there was a 11 reason to have a discussion. 12 We had entered a world where we quickly 13 discovered that Tory have became a valuable research 14 candidate due to his brain tumor and its location. 15 My husband was at the beginning of his 16 career as a physician. Maintaining his judgment, he 17 stated that we needed to bring the slides for review 18 to another pathologist. We were told that the grading 19 of his tumor would inevitably come back higher and 20 that we should not delay the start of treatment. 21 In the days that followed, we received 22 conflicting reports from different institutions about 129 1 the pathology and also the recommended treatments. 2 Some called it a high-grade malignancy, and others 3 called it a low-grade pilocystic astrocytoma with a 4 juvenile variant. 5 The second neuro-oncologist we met with 6 clearly stated that she would never consider giving 7 this eight-drug protocol to such a young child because 8 of the level of toxicity involved in this treatment. 9 The need for us to become educated, take charge, and 10 be Tory's advocate became clear. 11 She also told us that we needed to 12 understand our child would die from this tumor. Then 13 she added that the name of the game was to buy time 14 and buy more time, that one day there might be 15 effective treatments. My thoughts were, could new 16 treatments possibly be introduced quickly enough? I 17 really thought she was just giving us a party line. 18 Years later she would say that the first 19 time she met Tory, he looked as if he had been in a 20 bad train wreck. We were in a race with no road map 21 and no knowledge of anyone who made it to the finish 22 line successfully. 130 1 I asked if there were other parents we 2 could speak with. And I was told that the only 3 parents were those whose child had died. 4 Unable to reach a conclusion about 5 treatment, we decided to return to talk further with 6 Dr. Epstein, our neurosurgeon. We asked him what he 7 would do if this were his child. He told us that 8 based on what he saw and the conflicting reports, at 9 that time if this was, in fact, a high-grade tumor, 10 chemotherapy would not bring much benefit. 11 And Tory was too young for radiation, 12 although there were some involved with treatment that 13 did believe that radiation should have been 14 considered, despite his age. 15 He said given all of this, the 16 recommendation that he would make was to wait and 17 watch. We chose to trust his instincts about the 18 tumor being low-grade and to wait and watch. Although 19 this was clearly a risk, it was the road that we 20 chose. 21 In making this choice, our relationship 22 with Dr. Epstein, whom we trusted for his honesty, his 131 1 judgment, his wisdom, and his values, became 2 established. He did not treat Tory as a research 3 candidate but, instead, with dignity as our child. 4 Those were the characteristics of the 5 professionals who became Tory's treatment team over 6 time. These professionals were sometimes from 7 different institutions. 8 It is the ethical responsibility and needs 9 to be the culture of the treatment team to present all 10 information to parents regarding treatment options in 11 an unbiased, factual, and understandable manner, 12 sharing both the balance of potential benefits with 13 the potential consequences as well as the unknowns. 14 Parents depend on the treatment team and 15 the NIH to ensure that treatments offered to children 16 are safe and tested. It is critical that research 17 protocols and drugs be tested and be specifically 18 designed for children. 19 Our mantra and goal became to give Tory a 20 childhood one day at a time while trying to save his 21 life. To say those years were extremely difficult 22 would be a gross understatement. 132 1 In addition to the monumental stress of 2 having a critically ill child, families face stress 3 and obstacles negotiating with insurance companies 4 over approvals for ability to be seen by the necessary 5 specialists, approval for procedures and therapies 6 while also trying to go to work and maintain their 7 livelihood. 8 Somehow we forged ahead making decisions 9 as we were confronted with new challenges along the 10 way. And our journey evolved. It was, however, at 11 times long and unrelenting. 12 In November of 1989, Tory's symptoms 13 returned, indicating tumor recurrence. Within days, 14 he had another debulking of his tumor, insertion of a 15 VP shunt due to hydrocephalus, and a Broviac catheter 16 inserted. This time chemotherapy was necessary. 17 As we sat reviewing chemotherapy options 18 for treating low-grade tumors because we were still 19 choosing to following that path with a member of 20 Tory's neurosurgical team, he received a paper in the 21 mail as we sat there that was considered to be 22 anecdotal. 133 1 We looked over the paper as we sat with 2 him. Two children with low-grade tumors in California 3 were receiving the combination of vincristine and 4 carboplatinum for their tumors. Both were alive nine 5 months later. One tumor was stable, and the other had 6 become a little bit smaller. This was great news to 7 us. 8 That was how we chose chemotherapy. This 9 protocol later became very widely used when there is 10 no clear treatment course. Parents even want to hear 11 and consider the anecdotal reports. 12 Over the next 18 months, there were many 13 challenging clinical questions. Tory attended 14 preschool, bravely tolerating chemotherapy, never 15 choosing to complain in any way. His tumor size 16 remained stable. 17 At one point Tory experienced some very 18 worrisome neurological symptoms. At it was concluded 19 that the tumor was growing. As recommended, we met 20 with the radiation oncologist. 21 The next treatment would be for 22 hyperfractionated radiation to be administered two 134 1 times daily in very high doses. This would 2 significant impair his cognitive functioning. 3 After several days, to everyone's 4 surprise, the clinical symptoms suddenly began to 5 decrease until he then showed some clinical 6 improvement. Clinical symptoms in Tory's treatment 7 planning always carried great weight because MRIs 8 weren't providing us with specific enough information. 9 The plan for hyperfractionated radiation was stopped 10 shortly before it began. 11 Chemotherapy was completed in 1991, the 12 summer before Tory entered kindergarten. By this 13 point, we had become very emotionally attached to 14 chemotherapy, convinced that this was keeping Tory 15 healthy. In fact, we really lost sight of what we 16 were actually giving our child, and it became a way of 17 life. 18 We began to talk to our treatment team 19 about our idea to view this as a chronic disease 20 process that we would treat as needed. That wasn't 21 part of oncology language in 1991. Psychologically it 22 was easier for us to live with thinking about his 135 1 disease in this way. 2 Once again, we were reminded that, in 3 fact, we needed to understand that our child would die 4 of this tumor. We understood that. And we also 5 understood the need to roll with the punches. 6 Things were looking brighter for a while. 7 Tory remained healthy for about 16 months following 8 the completion of chemotherapy. In the late Fall of 9 1992, symptoms again returned. We were scared at this 10 point. Despite the passing years, the conflicts over 11 pathology and treatment choices were never resolved. 12 Tory underwent another tumor debulking, a 13 shunt revision, and insertion of a mediport catheter. 14 Again we decided to begin chemotherapy. However, at 15 this point Tory did not receive any benefits from 16 chemotherapy. And there were no new chemotherapies 17 being offered to him. 18 The tumor had become very cystic at this 19 point. Over the months that followed, he had frequent 20 needle aspirations of the tumor while we struggled 21 with the question of how to deal with his 22 deteriorating situation. 136 1 By early 1994, Tory was depending on 2 Decadron to decrease his symptoms and just to be able 3 to minimally function. The pain in his head and 4 vomiting were constant and intense. He could barely 5 walk. He had become withdrawn, sullen, and at times 6 aggressive. It appeared we were losing ground. 7 That spring we decided it was time to use 8 what we considered to be our last tool in this bite. 9 We scheduled another tumor debulking to be followed by 10 radiation. 11 By this time, hyperfractionated radiation 12 was no longer being recommended to us. Tory was now 13 a candidate for conformal radiation. Buying time and 14 making treatment decisions, we had hopefully spared 15 Tory some of the disabling effects of treatment. 16 We were prepared for a wide range of 17 devastating possibilities following surgery. We were 18 extremely fortunate, however, that he came through 19 surgery having a rapid recovery without those serious 20 consequences. 21 It remains unclear whether radiation would 22 prove beneficial for him due to the highly cystic 137 1 component of his tumor. And also radiation was being 2 considered most effective in higher-grade 3 malignancies. That was in July 1994. Fortunately, 4 radiation was highly effective in his bite. 5 I am proud to say that Tory is now 19 6 years old. He has been free of his tumor for the past 7 11 years. Tory just completed his first year at 8 Marist College in New York living independently on 9 campus as an accounting major. 10 His story has been an amazing journey for 11 our family. Tory's survival is both miraculous as 12 well as a testament to research, to finding optimum 13 medical care at each turning point. 14 Throughout the years, Tory demonstrated a 15 resilient spirit, character, courage, perseverance, 16 and strength that, in both positive and negative ways, 17 shaped the person he has become. There is not a 18 single day in his life that I am not extraordinarily 19 grateful for the gift of his life. 20 I wish I could honestly say that Tory's 21 medical journey ended there. Tory will continue to 22 face the secondary challenges and permanent 138 1 disabilities resulting from having had a brain tumor 2 and also the treatments he received. 3 These disabilities in a child who had not 4 been confronted with the battle of a brain tumor would 5 be devastating. Tory has been a pioneer in the 6 treatment of brain stem tumors. We focus on how 7 fortunate he is to be a survivor. 8 Resulting from radiation, Tory does not 9 produce growth hormone. He underwent eight years of 10 daily injection so that he could reach his adult 11 height. That was successful. However, we discovered 12 last month that at 19 years old, he has osteoporosis 13 secondary to some of his treatments. He may require 14 growth hormone injections for the rest of his life to 15 deal with this. 16 Additionally, he has a left-sided facial 17 paralysis, which is the result of the tumor location 18 and commonly occurs following surgery. In addition, 19 he has no corneal nerve function in his left eye, 20 which has over the years resulted in frequent 21 abrasions, scarring, and the loss of vision in that 22 eye. These issues have greatly altered his physical 139 1 appearance as well as his speech clarity and voice 2 quality. 3 At 15 years old, he elected to undergo a 4 series of 2 to 3 highly complex facial nerve 5 reconstruction surgeries and daily rehabilitation to 6 regain some movement in the left side of his face. 7 Even now I feel extremely conflicted about the choice 8 and the need given all he had been through for him to 9 go through these surgeries. 10 He has also had extensive dental and bone 11 development problems due to the paralysis in the left 12 side of his face. He also has no hearing in his left 13 ear. His gait and coordination are awkward, but he 14 compensates for these issues as best as he can. 15 Tory has always learned easily in school 16 and continues to have an excellent memory. He has 17 been in some very advanced level high school classes, 18 like calculus and Spanish honors V. He attends a 19 mainstream college, where he receives support services 20 from the campus learning specialists. 21 Had we made different treatment choices, 22 this would not have been the case. Yet, he could not 140 1 have succeeded academically without extensive supports 2 in and out of school to deal with slow processing 3 speed, challenges in his expressive written language, 4 inferential thinking, and executive functioning. 5 As parents, the skills we learned while 6 negotiating his medical care we later used to ensure 7 that his educational needs were appropriately met, 8 continuing always with the goal of ensuring the 9 quality of life he deserves to have. 10 As Tory goes through his life, advocacy 11 remains a primary focus of our day-to-day life. He 12 faces life with optimism, believing he can conquer the 13 world. 14 In his world, this translates into being 15 the next big sports agent for the Yankees or the NBA. 16 Right now he's just looking to get an internship in 17 one of their accounting departments. As parents, we 18 hope he will remain healthy. 19 While the challenges are inevitable, we 20 hope they will remain manageable. We hope he will 21 continue to meet people on his journey who will take 22 interest, show sensitivity and tolerance, and help 141 1 make his future gratifying for him. 2 Now our most immediate challenge is giving 3 him the skills and tools medically, educationally, 4 emotionally, and socially to take him into independent 5 young adulthood and continue to deal with the 6 late-term effects of his treatments. 7 In summary, the good news is through 8 research, successful treatment in pediatric cancer is 9 increasing. Research to increase survival rates, 10 reducing late-term effects, is critical. 11 Treatments must be improved to ensure that 12 we protect these children whenever possible from 13 long-term disabilities and ongoing medical problems 14 secondary to the treatments. Children need drugs 15 designed and tested specifically for them. 16 Treatment teams must recognize their 17 responsibility to present parents with all of the 18 treatment choices and facts in an ethically 19 responsible, informative, and non-biased way. This 20 value needs to be held as a high priority in the 21 treatment community. 22 Thank you for including parent input in 142 1 the presentations today. And I hope that this will 2 provide meaningful discussion for you. 3 (Applause.) 4 CHAIRMAN PRENTICE: Thank you very much, 5 Linda, for sharing a very compelling story with us. 6 I'd like now to invite Ron Honberg to come 7 up to the table. I will read his bio. He is 8 currently the National Director for Policy and Legal 9 Affairs at NAMI. In this capacity, he functions as a 10 resource to members, attorneys, and others on a 11 variety of legal and policy issues impacting on the 12 lives of people with severe mental illnesses. 13 He also works extensively on promoting 14 jail diversion, community reentry services, and 15 improved treatment for persons with severe mental 16 illnesses who come into contact with law enforcement 17 and/or correctional systems during periods of crisis. 18 He has worked for NAMI in a variety of 19 legal, governmental relations, and public policy roles 20 since 1988. He has a J.D. from University of 21 Maryland's School of Law and a Master's in rehab. 22 counseling. 143 1 Thank you very much, Ron, for agreeing to 2 speak with us. We look forward to your remarks. 3 MR. HONBERG: Thank you. 4 And I guess I want to start out by 5 thanking Linda. It's Linda, right? I didn't expect 6 to even talk about this, but you certainly I think 7 cause all of us to reflect in this room and I have to 8 admit caused particular reflection for me because my 9 wife and I have a daughter who just last week had her 10 23rd surgery, who was born with a genetic disorder, 11 and has had lots of neurosurgery and reconstructive 12 surgery, some of the same problems, including 13 hydrocephalus and growth deficiency and profound 14 hearing loss, fortunately not a brain tumor but just 15 reflecting on all the curves in the road and all of 16 the unexpected circumstances. 17 You know, the realization at times, even 18 though we have had wonderful physicians, they're not 19 all-knowing either. You sort of all learn as you go. 20 I guess more than anything -- and I heard 21 this very much in what you said -- how inspired you 22 are in seeing a child go through these kinds of things 144 1 and, yet, be so strong, it's just amazing to see the 2 strength of spirit. 3 I think you captured so well, really, both 4 the heartaches that parents go through and the hope 5 that exists, even sometimes when people don't give you 6 any hope. So I really wanted to thank you for that. 7 I'm actually here, as you heard, as an 8 advocate for people with serious mental illnesses. 9 NAMI is the nation's largest organization that 10 advocates for people with those illnesses: 11 schizophrenia, bipolar disorder, major depression. 12 Our membership is primarily people with 13 mental illnesses and their families. We have 14 membership throughout the country, most of whom are 15 involved in advocacy at state, local, and also at the 16 federal level. 17 I have to tell you that our members -- and 18 I don't mean this in any way disparagingly; I actually 19 mean this in a very positive way -- to some degree, 20 lots of them have been research groupies because they 21 have seen, they have recognized over the years that 22 research, particularly biomedical research, represents 145 1 the best hope for the future. 2 You know, 20-30 years ago a diagnosis of 3 schizophrenia was sort of a life sentence to a life 4 devoid of hope. And I think that our members to the 5 extent that they derived hope, it was through some of 6 the research breakthroughs that have occurred. 7 So that at our national convention every 8 year we have, the most popular sessions always are the 9 "Ask the Doctor" sessions, where you have the leading 10 researchers in schizophrenia research or bipolar 11 disorder, OCD, autism do presentations, people just 12 lining up, consumers and family members, to ask 13 questions. 14 You know, for many years, I have to say 15 there weren't a lot of questions raised about 16 research. The focus on research was very much we need 17 more of it. Every year we would go before Congress 18 and lobby for more money for NIMH. 19 When I started at NAMI, the NIMH research 20 budget was a pittance, I mean, a minuscule percentage 21 of what it is today. And we still are very, very 22 strong advocates for research. 146 1 I have to say there has also been to some 2 extent over the last five or six years a crisis of 3 confidence about the research enterprise. You know, 4 at least the recognition that while researchers are 5 very smart people and most of them are in it for the 6 right reasons, there are potential conflicts. 7 There are potential practices that may not 8 serve the best interest of people who participate as 9 human subjects, particularly those who are vulnerable, 10 people who may have impaired capacity from time to 11 time to understand the nature of the protocols they're 12 participating in and to express or to make judgments 13 about what is in their best interest. 14 There was a case back in 1998 or it was 15 late '90s anyway at UCLA that I think was pretty 16 highly publicized that raised serious questions not 17 only about informed consent but about sort of that 18 divide between what constitutes research and what 19 constitutes clinical practice. 20 It was a protocol that actually was I 21 think called a relapse study. It was a study where 22 people were taken off medications to determine whether 147 1 they needed those medications and to sort of evaluate 2 patterns of relapse. 3 The problems occurred because apparently 4 lots of the people, some of the people who 5 participated and their families didn't understand 6 that. And there was one situation that I am very 7 familiar with with a family, a very well-educated 8 family, I might add, that was not only shocked to find 9 out that this was a relapse protocol but even more 10 shocked to find out that when their son began to 11 relapse -- you know, relapse and psychiatry oftentimes 12 is very scary. I mean, a person decompensates. They 13 may suddenly stop trusting everyone who is around 14 them. They may engage in behaviors that they normally 15 wouldn't engage in. 16 The family as they saw their son 17 decompensating realized that no one at the research 18 institution was available to respond to their clinical 19 concerns. And it ultimately resulted in their son 20 becoming homeless after he pulled a knife on his 21 family, something that the son would never do and has 22 never done anything remotely approaching that since 148 1 then. He survived that. Another participant in that 2 protocol actually committed suicide. 3 Hindsight is always 20/20. When I looked 4 at that consent form, -- I'm thinking about what Dr. 5 Jones said -- yes, it was -- and I'm a lawyer -- very, 6 very difficult to understand. If you read the fine 7 print, perhaps you did understand that the protocol 8 involved removing the person from the medication. 9 But it wasn't easy to see. It certainly 10 wasn't written in lay person terminology. Again, not 11 trying to cast dispersions on or really talk too much 12 about that protocol it's been the subject of 13 litigation. It may have been recently settled. 14 When these kinds of problems occur, they 15 also represent opportunities for progress. So I guess 16 the question that I'm here to address to some extent 17 is, has there been any progress over the last five or 18 six years? 19 When the UCLA story broke, there were also 20 revelations of other types of protocols that, frankly, 21 were shocking to our members, at least were shocking 22 to me. I never realized they occurred, symptom 149 1 provocation studies, where people were actually 2 administered agents designed to provoke psychiatric 3 symptomatology. 4 Realization that the regulations that were 5 in place through the common rule and through the FDA 6 regulations really didn't address some of the issues 7 that are certainly very concerning to people with 8 mental illnesses, I don't think unique to people with 9 mental illnesses, around capacity assessment. 10 Were there mechanisms in place to even 11 evaluate whether people were capable of understanding 12 the natures of the protocols they were participating 13 in, the potential risks and benefits, and make 14 informed decisions? Was there any effort to determine 15 that? 16 And, beyond that, suppose there was a 17 determination that the person lacked capacity to 18 participate in research? What happened then? Would 19 the research still proceed? 20 None of that was addressed in regulations. 21 And so it was really, pardon the language, sort of a 22 crap shoot. I think it was sort of decided protocol 150 1 by protocol. There wasn't a whole lot of guidance for 2 IRBs. 3 About that time, a little bit later, -- 4 and I do want to digress quickly and acknowledge Adil 5 Shamoo, who is actually in the room. I haven't seen 6 him for years. Are you the Director of CIRCARE, Adil? 7 Adil actually when he served on the NAMI 8 board many years ago really taught me a lot of 9 whatever little I know about this subject. So it's a 10 delight to see him. He has been working at these 11 issues for years. 12 Shortly thereafter, I became involved in 13 an IRB. I served on the intermural research IRB at 14 NIMH. And the intramural research center does all of 15 the research within NIMH itself. And at the time, I 16 was the only lay person on there. I was the only 17 non-scientist, non-physician. 18 I have to say that I assume that NIMH, NIH 19 represent the best of the best and that, by and large, 20 what I saw during the years that I served on that IRB 21 were fairly positive. I think that there was an 22 increasing sensitivity each meeting to the issues that 151 1 vulnerable research subjects encounter and the need to 2 be very vigilant to those. 3 But it was still a very awkward dynamic 4 for my colleagues on that IRB because most of them 5 worked at NIMH. And they were actually evaluating 6 protocols that some of their colleagues were 7 presenting. 8 So it was, needless to say, a pretty 9 uncomfortable experience to have to raise questions or 10 even defer approval. In a couple of cases, we 11 actually rejected protocols. But they got better and 12 better at it to my gratification. 13 I brought something to that protocol, I 14 think. I brought sort of an awareness of the 15 day-to-day issues that people with mental illness 16 experienced. 17 On the other hand, particularly when I 18 started, I realized how deficient I was in really 19 understanding the science of the protocols. And I 20 have to say that the scientists, some of whom are some 21 of the most eminent scientists in the field of 22 psychiatry who were on that IRB, understood all of the 152 1 scientific aspects of the protocols they were 2 reviewing, but not all of them really understood the 3 types of day-to-day issues that people encountered and 4 what impact he protocol might have on people's 5 well-being, particularly when they leave the 6 institution. Many of these protocols were outpatient 7 protocols. So hopefully we all educated each other. 8 I can't say that there was any formal 9 training program at that point in time. And that was 10 something when I left the IRB I noted needed to 11 change. 12 So the question, has anything changed over 13 the last five or six years, I think when the UCLA 14 story broke, when some of the other stories broke 15 about the symptom provocation studies, et cetera, 16 there was a call for amending the common rule. 17 Interesting thing about the common rule -- 18 and this is something I learned from Adil as well -- 19 when the commission -- I guess it was called the 20 Belmont Commission -- in the late '70s studied issues 21 around human subjects research, they recommended 22 protections for certain classes of people, additional 153 1 protections, that they regarded as particularly 2 vulnerable, that being pregnant women, children, 3 fetuses, prisoners, and people with mental or 4 cognitive disabilities. 5 And, yet, when the common rule was first 6 published -- and I think it was in the early '80s -- 7 there were actually subparts included for all of those 8 populations except for people with mental and 9 cognitive disabilities. 10 The story that I have heard is that the 11 research community at that point was very 12 uncomfortable with a special subpart from people with 13 mental and cognitive disabilities because they felt it 14 would have a chilling effect on the ability to conduct 15 research. I am really not here to cast dispersions on 16 that. I think these were well-meaning objections that 17 were raised. 18 But I think we have to look at history and 19 ask ourselves if the lack of specific guidance in the 20 common rule or in the FDA regulations, for that 21 matter, about what you do, particularly when you're 22 conducting research involving people who may be 154 1 extremely vulnerable where there may be issues about 2 decisional capacity, what you do and how you conduct 3 those protocols, there's really very, very little 4 guidance in either the common rule or the FDA 5 regulations. 6 So do you rely on the research community 7 to do the right thing? Well, I would like to think 8 that in most cases, the research community does do the 9 right thing. 10 I felt that at NIMH, by and large, the IRB 11 that I sat on asked the right questions and pushed the 12 researchers, the principal investigators, most of whom 13 did so without protest, to put in the kind of 14 safeguards that are really needed in these types of 15 protocols, but I don't know that you can rely on good 16 faith and that kind of vigilance in all cases. 17 There are so many different studies taking 18 place around the country. There are so many different 19 types of research institutions. There are so many 20 potential conflicts of interest, including some that 21 we heard in the earlier panel, about the role that 22 industry plays in financing these protocols. 155 1 I'm a lawyer, but I'm not necessarily one 2 who is a firm believer in regulations, but I think in 3 this instance, it is time for Subpart E in the common 4 rule because I think there really does need to be 5 specific guidance, guidance for research involving 6 people with mental and cognitive disabilities, 7 guidance that balances the competing interests, that 8 establishes adequate protections for people to prevent 9 the kind of abuses that potentially can occur and at 10 the same time doesn't have a chilling effect on 11 research. Maybe I am a naive optimist. I think that 12 can happen. 13 Why hasn't it happened? Because there 14 have been some real efforts to try to do it. I think 15 of an example that I was involved in in Maryland. I 16 sat on an Attorney General's task force, as did Adil, 17 for that matter. The Attorney General of Maryland 18 and, actually, his deputy, Jack Schwartz, were really 19 interested in trying to enact legislation that 20 established adequate safeguards for people with mental 21 illnesses who participated as human subjects in 22 research. 156 1 It was a tough process over a year or two, 2 but ultimately the task force itself put out a report 3 that largely reflected if not complete consensus, then 4 at least something we were comfortable with the task 5 force putting out. 6 But it was never enacted in legislation. 7 Why? Because when a hearing took place, there was, 8 frankly, lots of disagreement, public disagreement, 9 public testimony expressing strong reservations from 10 both sides of the aisle, from the research community 11 saying, "Don't regulate us. For gosh sakes, whatever 12 you do, don't do this because you're going to prevent 13 us from being able to do research" and from people who 14 felt like when it came to research protections, we 15 needed the whole loaf. 16 There is one thing that I know I think 17 from all the years that I have been doing work on 18 Capitol Hill and work with our state organizations. 19 That is, there's one thing that legislators run from. 20 And that is controversy. As soon as they caught wind 21 that there was controversy around this, they didn't do 22 anything. And, as a consequence, there are no rules 157 1 in Maryland. 2 I have to say the National Bioethics 3 Advisory Commission, which sat during the Clinton 4 administration, which our executive director at the 5 time, Lori Flynn, sat on, also tried to hammer out 6 these issues. There was lots of public disagreement 7 but ultimately, you know, a report that did come out 8 of NBAC but never found its way into legislation. And 9 there have been other efforts as well. 10 What point am I trying to make here? I 11 really appreciate the efforts of people who feel very 12 strongly about these issues, to put these issues out 13 in the public, because, frankly, if they didn't do so, 14 I'm not sure we'd ever hear about them. I'm not sure 15 we ever would have ever heard about the UCLA study. 16 I'm not sure we would have ever heard about some of 17 the other problems that existed. 18 On the other hand, when it comes time to 19 legislating or regulating areas as complex as this, 20 I'm not sure that extremism on either side is going to 21 carry the day. We haven't learned that, certainly in 22 my field, in the mental health field. 158 1 It's not unique to the research 2 enterprise. We frequently, as the director of SAMHSA 3 once said, act like a circular firing squad. We start 4 shooting at each other. And we don't try to focus in 5 on that vast gray area where we can reach agreement. 6 In recognition and bringing it back to 7 this topic, if there were some guidelines in place, it 8 would be a heck of a lot better than we currently 9 have, where there are no guidelines. 10 So let me finish up by just discussing a 11 little bit some steps that I think can be taken to 12 better protect vulnerable individuals with mental or 13 cognitive disabilities who participate in human 14 subjects research without impeding the ability of 15 vitally important research to proceed. Again, we 16 always have to think about that balance. 17 A few steps, many of which are actually -- 18 you know, hindsight is always 20/20. NAMI does 19 actually have some fairly extensive policy in our 20 policy platform taking about setting forth protections 21 in human subjects research. I should have brought it 22 with me, but I didn't. Much of this is reflected in 159 1 that policy. 2 First of all, I think it's really 3 important that there be patient advocates independent 4 of the research institution available in all research 5 that is greater than minimum risk involving people 6 with mental or cognitive impairments. Research 7 participants, their families and advocates must be 8 informed about the patient advocate and how to contact 9 him or her. 10 The fact is, as I said, I think most 11 researchers are very sensitive to these issues, but 12 there may be inherent conflicts of interest, whether 13 those inherent conflicts of interest are financial or 14 attributable to professional ambition. There needs to 15 be an independent person, an independent advocate 16 whose job is solely to monitor and protect the best 17 interests of vulnerable research subjects. 18 Two, IRBs should contain a majority of 19 members who are independent of the research facility 20 who don't work there or are not related to someone who 21 works there. 22 Now, that wasn't the case at NIMH when I 160 1 served on the intramural center's IRB. And I realize 2 that, particularly in some research institutions, some 3 university settings, that may be very difficult. But 4 I think it's certainly something that we should 5 aspirationally strive for to minimize the potentially 6 negative impact of conflicts of interest. 7 One question I know that people in the 8 mental health field have grappled with, should IRBs 9 reviewing research involving people with mental and 10 cognitive impairments be required to have a certain 11 percentage of members who are knowledgeable about 12 these disorders? 13 At universities, oftentimes -- I don't 14 know if this has changed; I don't think so -- the IRBs 15 review a wide range of research in a number of 16 dissimilar areas, biomedical area. So an IRB will be 17 asked to review a cancer protocol, a diabetes 18 protocol, and a protocol on mental illness. 19 There's no guarantee that anybody sitting 20 on that IRB is even all that knowledgeable about 21 mental illness and the kind of issues that people who 22 suffer from those illnesses experience. 161 1 NAMI's position is that IRBs who regularly 2 review protocols involving research on mental illness 3 must include public participants who are consumers and 4 family members with direct and personal experience 5 with these illnesses. 6 I can't say that enough these individuals 7 bring perspectives to the table that are a product of 8 their own experiences, that no researcher, however 9 well-meaning, is going to necessarily understand. 10 We at one point actually instituted some 11 IRB training for our members. I am sad to say over 12 the last couple of years, we haven't done it. In 13 preparing for this presentation, I certainly resolved 14 in my own mind that we need to reinstitute that 15 because the fact of the matter is that consumers and 16 family members need to be helped to prepare for those 17 roles. But it's critically important that they be 18 given the opportunity to serve those roles. 19 I want to talk a little bit about capacity 20 assessment. I'm seeing the lime green sign. So I'm 21 going to have to talk very quickly, even more quickly 22 than I have already been talking, but I'm almost done. 162 1 In my opinion, whenever research is 2 greater than minimal risk, procedures must be in place 3 to assess capacity. We have come a long way. It's 4 possible now to assess capacity, to make informed 5 decisions and research protocols. There are lots of 6 folks out there who have been doing work on capacity 7 assessment. There are guidelines out there. 8 Again, there's not word one in the common 9 rule about capacity assessment or what to do if you as 10 a researcher determined that somebody may lack 11 capacity to make informed decisions. 12 Research advanced directives I think are 13 a promising technology we ought to think about, tools 14 that would give consumers the opportunity to in 15 advance communicate their preferences should they lose 16 capacity at some point in the research protocol, 17 including identifying who surrogate decision-makers 18 would be. 19 And then two more quick issues: informed 20 consent. You know, you can't necessarily legislate 21 informed consent, but you can certainly do whatever 22 you can to require, as it was discussed in one of the 163 1 earlier panels, the need to provide as much 2 information as possible in language that lay people 3 can understand and, beyond that, to engage in efforts 4 to sit with participants and their families and 5 explain to them about the protocols. 6 I'm afraid that oftentimes still doesn't 7 happen to the extent it should. If you're going to 8 err, you should err on the side of too much 9 information. 10 One thing I remember -- and there are some 11 examples where that happens. I saw some examples at 12 NIMH where that happened. It's maybe not something 13 you can legislate. It's maybe more a product of 14 training. 15 And, then finally, I want to finish up by 16 quickly addressing the inherent tension that exists 17 between research and clinical treatment, the fact that 18 research isn't clinical treatment, but things are so 19 desperate in terms of access to treatment for people 20 with mental illnesses. 21 Only about 20 percent of all people with 22 severe mental illnesses have access to even minimally 164 1 adequate treatment in this country. I've got to tell 2 you we're going in the wrong direction as Congress 3 looks at cutting $10 billion from Medicaid over the 4 next few years. 5 There's lots of incentives for people to 6 turn to research as their only way to get treatment. 7 And the sad reality is that oftentimes in research 8 protocols, people get better treatment and care than 9 they do in the mental health system. 10 Now, I don't need to tell you that there 11 are potentially significant coercive effects there. 12 And we need to be aware of those. I think researchers 13 need to be very clear that what they are providing is 14 not treatment, that the primary purpose is research. 15 And at the same time, my last point, -- 16 and I'll stop because I have exceeded the one minute; 17 I know that -- researchers do have responsibility for 18 protecting the clinical well-being of vulnerable 19 consumers. 20 I think that that UCLA protocol, the 21 problems there, beyond everything else, were clinical 22 failures. But there were no mechanisms in place when 165 1 people deteriorated to respond to their needs. 2 And so research investigators in NAMI's 3 opinion have an obligation to ensure that people get 4 treatment while they're participating and must also 5 engage in good faith efforts to link people to 6 treatment when they leave research protocols, 7 particularly when they are symptomatic. 8 All research protocols involving people 9 with serious mental illnesses should also include 10 mechanisms and procedures for responding to 11 psychiatric emergencies, which occur quite frequently. 12 So, in closing, I apologize for exceeding 13 my time. I hope I didn't wander too much with this. 14 If there is one enduring message I want to leave you 15 with, I really think it's time for a renewed effort to 16 try to develop regulatory guidance around some of 17 these issues I have raised. I'm just not confident 18 that we can leave these very complicated types of 19 judgments and decisions and procedures to the research 20 community, however well-meaning they may be. 21 Thank you very much. 22 (Applause.) 166 1 CHAIRMAN PRENTICE: Thank you, Ron. 2 Would the three panelists please assemble 3 at the front table? We're going to cut lunch short by 4 probably 20 minutes. So we're going to have about 20 5 minutes for discussion if that is acceptable to the 6 members of SACHRP. I'm sure you can eat lunch in a 7 quicker period than one hour. 8 While you are assembling, I will simply 9 indicate that I am going to exert Chairman's 10 prerogative and not ask questions because I am going 11 to allow all the rest of the panelists to ask 12 questions. But I will make one statement. 13 And that is OHRP is in the process of 14 pursuing a Subpart E. It is in the review stages at 15 the moment. It's going to take some time obviously to 16 reach the point where it would be actually published 17 for comment in the Federal Register, but it's time 18 that we did have additional protections for 19 individuals who are, I guess the term now is, 20 cognitively impaired or decisionally impaired, as 21 opposed to mentally ill. So I think we can look 22 forward to that at some point in the future. 167 1 (Applause.) 2 CHAIRMAN PRENTICE: Yes? 3 MEMBER BARNES: I am just wondering what 4 the process is and whether our input is going to be 5 asked before the thing is published in the Federal 6 Register. 7 EXECUTIVE SECRETARY SCHWETZ: Before it 8 goes to the Federal Register you're saying? Well, I 9 don't think we have normally shared draft guidance 10 with SACHRP before it goes to the Federal Register. 11 We share it internally with the various agencies, but 12 it's a good question mark. The answer is normally we 13 wouldn't, but that's something that we would have to 14 look at, how that could be fit in. 15 MEMBER BARNES: I am not saying that you 16 need to or not. I guess all I'm saying is that if you 17 need or would like any input from any of us, then I 18 think that that is something that we could try to help 19 you with -- that's all -- or help whoever is working 20 on it within SACHRP, even if it's only a series of 21 preliminarily sort of bouncing ideas off of us as an 22 advisory group or that sort of thing. 168 1 EXECUTIVE SECRETARY SCHWETZ: Thank you 2 very much, Mark. 3 CHAIRMAN PRENTICE: Okay. You had your 4 hands up at the same time. We'll go with Susan, then 5 Celia. 6 MEMBER KORNETSKY: Thank you all very 7 much. 8 My question is for Wanda. You may be able 9 to answer this. You may not. It's been some time now 10 that NIH grant applications, at least the proposals 11 and the continuing progress reports, asked for 12 specifically whether women will be included and 13 minorities and justifications why they would or 14 wouldn't. And then also they have fancy little charts 15 that ask for when patients are recruited. 16 I don't mean this sort of glibly, but what 17 really happens with that? I mean, are study sections 18 reviewing that? Are there comments made back that 19 this is not adequate? Is it just, "Okay. Now we're 20 tracking this"? What happens with that information? 21 DR. W. JONES: I do know that it is 22 "tracked." It's reported on an annual basis. But 169 1 whether study sections see it I have no idea. Whether 2 there is any role for those data in feedback, 3 evaluation, that sort of thing, I have no idea. 4 That would be a question for Dr. Vivian 5 Pinn at the Office of Research on Women's Health, 6 which is specifically charged with that tracking and 7 that work on the NIH-funded research. 8 MEMBER KORNETSKY: It is an interesting 9 question. I mean, I hate to use the word sort of 10 window dressing, but you brought up some very 11 important issues about research and the need for data 12 to come out of it that shows these differences. And 13 you would think that that would be a wonderful 14 opportunity to make sure that that really is 15 happening. 16 Just to track it to me means nothing. I'm 17 not blaming you. But I think it's important. It's a 18 good opportunity to really have some movement in that 19 area, at least for things that are federally funded 20 through NIH. 21 DR. W. JONES: I totally agree with you. 22 CHAIRMAN PRENTICE: Celia? 170 1 MEMBER FISHER: Yes. I want to get back 2 a little to the issue of Subpart E but also want to 3 thank all of you for great, very meaningful 4 presentations. 5 One of the reasons I think it might be 6 helpful for SACHRP to have some kind of review perhaps 7 of what is going to come in the Federal Register is 8 that yesterday, when Subpart A was being discussed, -- 9 and we didn't get to the minimal risk issues, but one 10 of the questions that was asked by the Subpart A group 11 was, is there a need for harmonization across the 12 different subparts? 13 One of the issues that I was thinking 14 about was that there can be special reasons to be more 15 conservative for vulnerable groups. But since there 16 are no kind of identified vulnerable adult groups 17 other than prisoners and pregnant women, that, in 18 fact, the question of harmonization needs to be 19 addressed in a very different way than if there were 20 safeguards for vulnerable adults that were in there. 21 So in that sense, depending upon the 22 timing, I think that that and other issues about 171 1 informed consent that Subpart A is going to be 2 addressing, it is going to be important for us to have 3 some understanding of where a Subpart E might be going 4 so that we could adequately address those issues. 5 I have done research myself with mentally 6 impaired population in terms of the ability to give 7 informed consent. And from an ethical perspective, I 8 have been very concerned about how one balances the 9 obligation to respect the autonomy rights of 10 individuals with impaired capacity and at the same 11 time protect them from exploitation as well as making 12 poor decisions. 13 One of the concerns I think from those who 14 want protections and at the same time are wary about 15 them is whether or not, number one, you're 16 stigmatizing a population. And the assumption that 17 there are measures that can adequately assess whether 18 or not somebody is or is not cognitively impaired, I 19 think that there are questions in that. 20 I mean, I think there's been wonderful 21 work by Paul Applaban and his colleagues with respect 22 to schizophrenia and depression. But even Paul -- and 172 1 he's a wonderful ethicist -- relates the fact that you 2 may be impaired for some types of decisions but not 3 for others. I think that that is very critical to 4 address. 5 There are also individuals whose cognitive 6 capacity is transient. You know, I don't know if 7 Subpart E is going to be addressing those issues, but 8 especially in the schizophrenic population, for 9 example, are you under Subpart E sometimes? 10 You know, it reminds me of some of the 11 problems we're seeing with C. You know, you're in 12 prison, and you're not in prison and you are in 13 prison. What regulations are you supposed to go 14 under? 15 So I think there's lots of issues that 16 need to be address there. So I would like some 17 feedback in that regard so we can move ahead and also 18 that Subpart E, in and of itself, may not be a 19 panacea, even though it is very important to protect 20 these populations. 21 So I think we want to be very careful 22 about that and who is going to be included in Subpart 173 1 E. 2 MR. HONBERG: Just to comment very 3 quickly. I think you raise very, very legitimate 4 concerns. And certainly I hope I didn't convey the 5 impression that I felt that all people with mental 6 illnesses who participate in research have impaired 7 capacity or that you even necessarily have to assess 8 capacity in all cases. 9 I think there are many, many people -- you 10 know, recovery is the mantra in our field today. 11 Many, many people can recover. I think the tricky 12 think is that, again, we're talking about fluctuating 13 capacity. 14 And the way that groups that have looked 15 at this have sort of tried to address it in the past, 16 again, just thinking about the Maryland Attorney 17 General's group, thinking about NBAC, was the greater 18 the risk, the more vigilant you got in sort of looking 19 at capacity. 20 I mean, that is probably to some degree a 21 no-brainer. If we're talking about minimal risk or I 22 guess in the children's subpart, there is a category, 174 1 "Minor Increment Beyond Minimal Risk." 2 Perhaps your concerns about capacity, 3 while they still should exist, are not as heightened 4 as if you're talking about risky research and 5 particularly research with high risk that has no 6 direct benefit to the individual. 7 In my opinion, if you're going to err 8 there, you err on the side of caution. You err on the 9 side of caution in at least asking questions about 10 capacity and making sure that you think very carefully 11 about that at the front end and throughout the 12 research protocol. 13 Then I also think by having some of the 14 other mechanisms in place, like an independent 15 advocate, like a research advanced directive that 16 includes the designation of a surrogate 17 decision-maker, you're also to some degree covering 18 your bases. There are no easy answers. It speaks to 19 how complex these issues are. 20 I would also agree with what I think you 21 are saying, which is that while I'm really glad to 22 hear that Subpart E is in development, it is a very 175 1 positive thing, and we want to be as helpful as we 2 can, I do think that eliciting some input from the 3 various stakeholder groups, even though that can make 4 things a little complicated, is critically important. 5 Otherwise there's going to be a firestorm as soon as 6 it comes out. And you may ultimately be impaired, if 7 I can use that word, in achieving what you want to. 8 So I think not only because you have a 9 great deal of expertise on SACHRP and some of the 10 other groups but also because some vetting is awfully 11 important when it comes to an issue like this, I think 12 that transparency is important in developing a Subpart 13 E. 14 CHAIRMAN PRENTICE: Susan? 15 MEMBER WEINER: One theme that at least 16 two of the speakers addressed this morning or 17 indirectly, actually, is the relationship between 18 research and treatment and the ambiguity that exists 19 in many people's minds between research and treatment 20 and how that affects what consent means. 21 This is an issue that I think is 22 particularly important for the subcommittees to 176 1 address. It's not clear at all from the get-go what 2 should be in a consent form if your only option for 3 treatment consists of enrolling a child or yourself in 4 a research protocol. 5 I think that the balance to that, it's 6 true that it's better to err on the side of more 7 information. And it's always unacceptable to be 8 deceptive. But I think it makes it even more real 9 that the component analysis issue that we talked about 10 before; that is, that there are procedures that have 11 only research intent and are not therapeutic in intent 12 at all. 13 I think that that is the important thing 14 we have to keep in mind as we address consent process 15 and as we address how to modify these regulations. 16 CHAIRMAN PRENTICE: Susan? Nancy? 17 MEMBER JONES: I have a question for the 18 other Dr. Jones about the adequacy of Subpart B and 19 sort of going along with what Susan's question was 20 about how we are effecting change in the research 21 community to actually rethink how they're doing the 22 research because there are those precedents. 177 1 I was one of those ones that learned about 2 the 70-kilogram white male as the perfect test for 3 human subject research. And so it's almost like that 4 you have to morph to really effect change. 5 I know Susan addressed whether or not we 6 were being effective in just having it as a 7 requirement that somewhere on the NIH application, you 8 have to fill it out. 9 So I guess I have two questions. One, you 10 know, in looking at Subpart B and the protections for 11 pregnant women, is it adequate or does the way that we 12 look at it need to be changed so we can be inclusive 13 of women in research? 14 And, secondly, how can we effectively 15 change the research community to rethink on some of 16 the dramatic change that's needed to do effective 17 research in these populations? 18 DR. W. JONES: Easy questions. What's our 19 ending time? No. Just kidding. 20 CHAIRMAN PRENTICE: How about three 21 minutes from now? 22 DR. W. JONES: Okay. First, a disclaimer. 178 1 I'm really not the kind of doctor that helps anybody. 2 (Laughter.) 3 DR. W. JONES: I've just been in 4 government for too long. But with regard to Subpart 5 E, I had been involved early on in the changes that 6 were driven toward spousal consent, you know, all of 7 those restrictions on pregnant women. And on the 8 revisions that respected even pregnant women's 9 autonomy, their capacity to make the decision, you 10 know, the role that, sure, family, the father, if 11 there's a father in the picture. 12 And this was a barrier. This was one of 13 the issues with the 076 trials, that women were 14 excluded from participating in the HIV 076 trials 15 because a father had died or was simply not in the 16 picture. They were prohibited from participating. So 17 the Subpart B revision has remedied that. 18 Some would argue that women should be 19 given complete autonomy here, that whatever you were 20 doing, whether it is for the women's health, for fetal 21 health, you have to intervene through the woman. So 22 she should have complete autonomy. 179 1 I think there is still a role for the 2 system, for caution, because of the breaks, the human 3 chain that is still there in all parts in what I call 4 the research industrial complex, whether it's 5 federally funded, whether it's privately funded, or 6 what have you, that at least poses the question and 7 demands a higher standard of scrutiny and of 8 responsibility for pregnant women in research. 9 You know, changing the community, changing 10 the attitude, it's like shifting culture in many 11 respects. And I think incentive works better than 12 punishment. 13 I think the proactive stance that OHRP has 14 taken in getting out there with some training and 15 other things, you know, I would like to see a day that 16 the IRB is a partner in research and not this villain 17 that is keeping me from winning my Nobel Prize or 18 whatever the issue is because that is the problem. 19 And until we begin really incentivizing a 20 shift and until somehow researchers' issues and 21 problems in getting approvals is actually recognized 22 by funders because maybe that's another avenue to look 180 1 at, I am not sure we are going to have a great success 2 in changing that culture of research at all costs. 3 CHAIRMAN PRENTICE: Okay. I would like 4 thank the panelists for their very informative 5 presentations. I really wish we had more time. We 6 have other panel discussions this afternoon. And 7 we're going to have a wrap-up. So we may have more 8 time to ask questions at that particular time. 9 I would like to reconvene at 5 after 1:00. 10 So I'm cutting your lunch short by 15 minutes if that 11 is acceptable to everybody. So let's thank our 12 panelists. 13 (Applause.) 14 (Whereupon, at 12:22 p.m., the foregoing 15 matter was recessed for lunch, to reconvene at 1:05 16 p.m. the same day.) 17 18 19 20 21 22 181 1 A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 2 (1:12 p.m.) 3 CHAIRMAN PRENTICE: For purposes of the 4 record, I want to clarify the status of initiatives 5 relative to Subpart E. In the works is something 6 called an advanced notice of public rulemaking. 7 And what this means is that this ANPR will 8 be published in the Federal Register asking questions 9 such as "Should there be a Subpart E? Is there a need 10 for a Subpart E? What should it look like?" 11 So I don't want to give people the 12 impression that there was already a draft document 13 that represents the thinking of what Subpart E ought 14 to look like. This is the first step to get a Subpart 15 E. So I wanted to make sure that everybody understood 16 that. 17 Obviously SACHRP will certainly have input 18 in terms of its publication in the Federal Register. 19 You're perfectly free as SACHRP members to comment on 20 it. And, of course, you know you're perfectly free at 21 any SACHRP meeting to decide what future agendas 22 should look like. So it's very clear that you can 182 1 have as much input I think as you wish. 2 So with that clarification out of the way, 3 I would like to begin the first panel of the 4 afternoon. We're going to change the order slightly 5 because Dr. Henderson is on his way, apparently caught 6 up in traffic. So we will go with the second 7 individual on the panel. That is Dr. Cora Marrett. 8 And while she comes up to the table -- and 9 she is already up there -- I am going to -- she has 10 already got this system down. 11 (Laughter.) 12 CHAIRMAN PRENTICE: I am going to go ahead 13 and briefly give you something about her. She joined 14 the University of Wisconsin system as a Senior Vice 15 President for Academic Affairs in 2001. Before that, 16 she was the Vice Chancellor of Academic Affairs and 17 Provost at the University of Massachusetts in Amherst. 18 She has had faculty appointments at a 19 number of different universities that are well-known 20 to us, including the University of North Carolina at 21 Chapel Hill. She was an Assistant Director for the 22 Social, Behavioral, and Economic Sciences at the NSF 183 1 and chosen after a national search for a permanent 2 head. 3 Her academic background includes a B.A. 4 degree from Virginia University, M.A. and Ph.D. 5 degrees from University of Wisconsin-Madison and all 6 in sociology. So she's obviously well-versed in 7 sociology. And she's a member of a number of 8 different boards. 9 Welcome, Dr. Marrett. We're looking 10 forward to your comments. I think you know the format 11 here. 12 DR. MARRETT: I think I do. Thank you 13 very much. 14 CHAIRMAN PRENTICE: Great. Thank you. 15 PANEL 3: PERSPECTIVES OF RESEARCH SUBJECTS, 16 REPRESENTATIVES AND ADVOCATES 17 DR. MARRETT: From the National Center for 18 Bioethics at Tuskegee University comes this 19 observation. For many African Americans, the syphilis 20 study exacerbated fears of medical exploration. 21 Today, more than a quarter century after the study was 22 halted, apprehensions still linger. 184 1 Too many African Americans avoid 2 participating in important clinical trials, refrain 3 from donating blood, and even refuse routine medical 4 care. 5 Now, this observation implies that the 6 Tuskegee effect continues to shape responses to the 7 biomedical system by African Americans. It rests on 8 three facts. First, many African Americans interpret 9 the Tuskegee untreated syphilis study as medical 10 research gone awry. Second, African Americans tend to 11 express greater mistrust of medical care and 12 biomedical research than do white Americans. And, 13 third, African Americans overall participate less 14 frequently in biomedical research than do white 15 Americans. 16 Those are the facts. But the line of 17 reasoning centered on the Tuskegee effect cannot 18 explain why African Americans with no knowledge of the 19 Tuskegee study do not participate in clinical trials 20 or why some with that knowledge do. 21 That line of reasoning centered on the 22 Tuskegee effect treats the African American population 185 1 as rather undifferentiated. And, finally, that line 2 of reasoning suggests that few actions can be taken to 3 modify levels of participation. 4 I want to say just a little bit because I 5 know most people are quite familiar with the Tuskegee 6 study, a little about its contours, the reactions to 7 it in the 1970s and later, and then something about 8 what does a series of research studies show about 9 African Americans in biomedical research, and then if 10 there's time a few comments about some matters that 11 might deserve attention. 12 As I said, I'm not going to try to outline 13 all of the aspects of the Tuskegee study. As I think 14 all of you are familiar with, in the southern U.S. of 15 the 1920s, syphilis was a key problem in public 16 health. The treatments with mercury, for example, 17 proved to be very ineffective. But even the 18 treatments for poor residents were reduced 19 significantly when the Rosenwald fund, which was a key 20 contributor, cut its support in the wake of the Great 21 Depression. 22 The Public Health Service, a collaborator 186 1 with the Rosenwald fund, decided that the project 2 could be continued if it centered on the effects of 3 untreated syphilis. The Public Health Service then 4 limited its focus to Macon County, Alabama, which 5 actually was only one of the several counties involved 6 with the initial study. 7 In 1932, it launched in concert with what 8 was then Tuskegee Institute a study of 600 black men, 9 399 with syphilis and 201 without the disease. The 10 explanation given to the participants was they were 11 being treated for bad blood. A local colloquialism 12 covering problems that could range from tiredness to 13 venereal disease. 14 In exchange for their participation, the 15 men received medical checkups, meals, and burial 16 insurance, all free of charge. The study, originally 17 conceived as a six-month project, was recast to 18 continue to the death of the participants. And, in 19 fact, it was not terminated until 1972. That 20 termination resulted from the public response to a 21 story on the study that the New York Times published 22 that year. 187 1 By the time the study was terminated, 2 several of the men had died but not before they had 3 infected their wives and, hence, their offspring. 4 But attention to the study did not end in 5 the 1970s. The ethics of the case continued to spur 6 discussion. In fact, what emerged was the view that 7 the fundamental ethical flaw in the study lay in its 8 failure to allow treatment over the years to the 9 subjects. 10 They were not given penicillin, a drug 11 found in 1947 to be effective against syphilis. In 12 fact, the Public Health Service arranged to have the 13 men excluded from a campaign that Macon County, 14 Alabama waged to wipe out venereal disease and 15 excluded from the requirement by draft boards that all 16 draftees would be treated for syphilis. Those who 17 were drafted were supposed to be tested and treated. 18 And this group was excluded from that requirement. 19 The Tuskegee study remained before the 20 public through the activities that let President 21 Clinton in 1997 to issue an apology before the nation. 22 They remained before the public through the 188 1 fictionalized account from Home Box Office that year 2 with an account "Miss Evers' Boys" and through 3 periodic accounts in the news media. 4 In fact, in 2002, National Public Radio 5 reprised to the history with a story entitled 6 "Remembering Tuskegee: Syphilis Study Still Provokes 7 Disbelief and Sadness." 8 Now, given the high visibility of the 9 study and the attention it still draws in many 10 circles, an argument about a continuing Tuskegee 11 effect might seem defensible. But, as I hope to 12 demonstrate, the support for that argument is quite 13 mixed. 14 Let me say a bit, then, about the 15 literature, the studies about the Tuskegee study, and 16 knowledge of it. There's a fairly extensive 17 literature about what that knowledge is among African 18 Americans. And it tends to show that African 19 Americans are more likely than white Americans to 20 recognize the study. 21 For example, a survey undertaken in 22 '98-'99 of a random sample in Detroit, in that 189 1 particular study, 81 percent of the African Americans 2 and 28 percent of the whites had some knowledge of the 3 Tuskegee study. Importantly, people with such 4 knowledge expressed little trust in researchers. And 5 this was particularly true for the African American 6 respondents, for whom knowledge about the study or 7 strongly on their attitudes towards medical research 8 and researchers. 9 Now, recognizing the phrase "Tuskegee 10 study" need not mean understanding accurately its 11 features. This is exemplified in a small-scale study 12 with African American outpatients at an urban 13 hospital. That study found that they understood the 14 Tuskegee study had violated human rights but were very 15 misinformed about the historical facts. Larger 16 studies affirmed the same finding. 17 One such analysis actually published 18 earlier this year is based on a survey of African 19 American and white adults in Baltimore. That study 20 found that most of the respondents, 58 percent, had 21 not heard of the Tuskegee study. And African 22 Americans in that particular survey were no more 190 1 likely than whites to indicate any awareness. 2 Of those who had heard of the study, most 3 knew the decade in which it began, but sizeable 4 fractions of blacks and whites believed it ended in 5 the 1950s. 6 Among the African Americans familiar with 7 the study, most, 75 percent, believed the men had been 8 given syphilis by the research team. Just over half 9 of the whites, 53 percent, shared this belief. 10 Now, the team, the research team, from 11 Baltimore examined mistrust of medical care and the 12 conditions associated with it. It showed higher 13 degrees of mistrust among African Americans than among 14 whites at every level of education, age, and income. 15 But the mistrust could not be attributed 16 to awareness of the Tuskegee study. In fact, those 17 particular researchers came to the conclusion that it 18 is time we move beyond Tuskegee as a catch-all. 19 Another study of residents 50 years old 20 and older further justifies a look beyond Tuskegee. 21 The analysts wanted to know if racial differences 22 existed in the willingness of participants or 191 1 residents to participate in clinical trials. Should 2 these individuals be found to have cancer? So this 3 was a population. You're asking, "Would you be 4 willing?" 5 A pivotal question for that particular 6 study, would knowledge of the Tuskegee study affect 7 especially the responses of African Americans? There 8 were racial differences in willingness to participate, 9 but those differences reflected primarily variations 10 in the ages and incomes of the African Americans and 11 whites in the sample. 12 With reference to the Tuskegee study, 13 knowledge about it was not different for the two 14 racial groups. Then what can we say about 15 participation? Well, the results from these recent 16 studies suggest that the Tuskegee effect perhaps has 17 been attenuated or operates in rather indirect ways on 18 patterns of participation. And they call attention to 19 other influences that possibly have more direct 20 effects. 21 The studies on race and participation in 22 medical research suggest a picture that is somewhat 192 1 complex. In the case of cancer trials, for example, 2 the National Cancer Institute, of course, provides the 3 information on who participates, at least in the 4 trials run through the clinical trials cooperative 5 groups, the networks of researchers that NCI funds. 6 In these trials, the participation of 7 African Americans tends to be proportional to the 8 incidence of cancer as measured by the number of new 9 cases per year within that population. There are 10 differences, however, by age group. 11 Up to 29 years of age, the involvement of 12 African Americans does not differ significantly from 13 that of white Americans. But between ages 30 and 79, 14 fewer African Americans than whites, non-Hispanic 15 whites, in particular, participate in such trials. 16 Race alone rarely counts for rates and 17 patterns of participation. Consider a small-scale 18 study from a couple of years ago from Duke University 19 in which it looked at recruitment to clinical trials. 20 What they did of the potential recruits, more whites, 21 46 percent, than African Americans, 31 percent, agreed 22 to join the trials. 193 1 But the two groups were quite different in 2 income and education. They were drawn from two 3 different clinics. One of the clinics drew from a 4 low-income population in the region. The other did 5 not. 6 The conclusion suggested by these authors 7 is that recruitment centered in race alone can be 8 ineffectual. Rather, interventions that target 9 education and income may increase the recruitment of 10 African American patients into clinical trials. 11 Persons of low-income and educational 12 status are less likely than their more advantaged 13 counterparts to participate in cancer clinical trials. 14 Because these status characteristics, 15 income and education, low income and low education, 16 are found more frequently among African Americans, 17 clinical trials for adults with cancer tend to have 18 relatively few African Americans. 19 Income and education are associated with 20 participation, but changes in participation require 21 more than a look at socioeconomic characteristics. In 22 other words, the reach to a broader cadre does not 194 1 demand that we must wait for an improvement in income 2 and education. 3 What, then, are some of the kinds of 4 things that affect other things affecting 5 participation? Recurring in this material is the 6 assertion that trust matters. A national sample found 7 that African Americans more than whites wondered if 8 their physician would fully explain a given research 9 project or seek to reduce the risks to participants. 10 Interestingly, this particular difference 11 remained, even when the black and white respondents 12 were compared in terms of education and income. 13 If trust matters, interestingly, there are 14 suggestions that trust can be built. We see this 15 through different projects in which there has been 16 recruitment through networks, networks researchers 17 have established, networks with outreach workers, 18 networks that use community boards and others to 19 interpret what is going on. 20 Trust can depend on what is communicated. 21 There was a group, a set of focus groups assembled a 22 few years ago in Alabama, a group that had very little 195 1 knowledge about the nature of clinical trials. They 2 indicated, however, they would participate if they 3 received adequate information regarding the purposes 4 and the benefits of the trial. 5 Just possibly, the need is more than 6 information relevant to a particular protocol. 7 Several advocates suggest there is a need for a 8 broad-gauged community education. And consider, a 9 fairly lengthy quote, but I'll give the whole one, -- 10 this is a statement -- "Members of the public are 11 unlikely to read scientific journals and may not 12 always recognize the links between medical research 13 and medical practice. Biomedical researchers may want 14 to make this connection clearer in their reporting and 15 may want to present their findings in more public 16 forums, such as newspaper and television news. 17 Physicians may want to explain how their practice is 18 informed by research and indicate how the public's 19 participation in research has made these practices 20 possible. By taking these steps, researchers and 21 physicians may display a better face of biomedical 22 research and raise the general awareness of the need 196 1 for participation." 2 Now, perhaps the survey I mentioned 3 earlier of Baltimore residents has implications for 4 information and education. The respondents were asked 5 about the Tuskegee study. Do you think it is possible 6 for a study like this to occur today? 7 Most blacks, 77 percent, and many whites, 8 47 percent, said yes, we think this could happen 9 today. That response could signal a profound distrust 10 of the medical research system. Alternatively, it 11 could reflect limited knowledge about the policies and 12 practices put in place post the Tuskegee study. 13 Obviously I have no time, nor would there 14 be anything for me to add if I said there have been 15 these changes in the infrastructure. The comment 16 here, though, is that knowledge about what has 17 happened in the infrastructure, the system of 18 protections is not always widely disbursed. And 19 without other ways for communication, there will 20 probably continue to be these questions of some idea 21 that it could happen again. 22 Now, there are these matters about how. 197 1 It's not just a matter of trust, however. In that 2 small study in an urban hospital, the respondents did 3 express mistrust, but they also expressed what had 4 happened to them personally. And without changes in 5 the way in which people are being treated, it will 6 also mean, then, that there will be reverberations in 7 response to what happens on the research side. 8 There isn't time. If there were, I would 9 say more about the other side of the picture, though. 10 All of what I've talked about so far is what explains 11 the limited participation. 12 Yet, there are participants. There are 13 volunteers. And there is a need, then, for far better 14 information to be gathered on what are the conditions 15 that lead African Americans to participate in research 16 and to have those who are participants to share their 17 experiences with others. 18 We know from some of the material that the 19 reasons for participation are not different from other 20 volunteers. These are people who often have had a 21 friend or a relative with a given illness. They know 22 the importance of research for improvements and 198 1 understand that research is not of a single stripe. 2 In conclusion, the suggestions here have 3 to do with the significant improvements in 4 communication about what does take place, recognizing 5 the sorts of concerns that might continue to exist. 6 But if communication is critical for protecting human 7 participants and advancing knowledge and practice, 8 then the broadening of public discourse is vital. 9 Thank you. 10 (Applause.) 11 CHAIRMAN PRENTICE: Thank you very much 12 for those very insightful comments. 13 I would like to now invite our next 14 speaker, Darrell Forney, to come up. And as he is 15 doing so, I will tell you a little bit about him. He 16 is a graduate of the University of Texas-Austin with 17 a B.A. in microbiology. He has taken a lot of course 18 work at Hopkins School of Professional Studies and 19 Business and Education. 20 Currently he is a senior research program 21 coordinator in the HIV/AIDS Outcome program at Hopkins 22 School of Medicine. He is a co-author on research 199 1 publications dealing with AIDS. And before that, he 2 was employed in the cancer registry with the 3 University of Maryland School of Medicine. 4 Now, probably more importantly for us 5 today, since 1996 as a research study volunteer, he 6 has participated in over ten research studies. And 7 becoming a study participant emanates from personal 8 interest in the use of humans in investigational 9 clinical research trials. 10 And as a minority, he has sought to 11 understand his personal reservations and those voiced 12 by other minorities towards participation as 13 volunteers for research investigation. 14 So we have a nice sequence here in that 15 Cora talked about the legacy of Tuskegee and the 16 Tuskegee effect and now we have Darrell as a 17 well-educated African American who sought to 18 participate in clinical trials in order to come to 19 grips with some of these issues. 20 So welcome. And we're looking forward to 21 your remarks. 22 MR. FORNEY: First I would like to thank 200 1 Dr. Schwetz and Dr. Prentice for inviting me to 2 participate in this. And also, too, I would like to 3 say to Dr. Marrett, it's nice to follow you. 4 Again, I am an individual who early in 5 life decided I wanted to enter into the medical field. 6 One of the things as a young African American growing 7 up in Texas in the South as I became more aware of 8 science was the Tuskegee study. That was something 9 that resonated within the community. 10 As I furthered my education and once I 11 moved from Texas to Baltimore, began working in 12 research, coming to Johns Hopkins, working in the 13 Johns Hopkins University AIDS Service, where the 14 population of our HIV-infected population is actually 15 70 percent African Americans, basically mirrors the 16 population of Baltimore, which is basically a city 17 that has an African American population of 70 percent. 18 Seeing that there were sponsored clinical 19 trials being conducted within this context and that 20 African Americans were the population who were being 21 targeted, teat increased my interest in human research 22 protection but also to the use of humans in research 201 1 clinical trials. 2 For myself, there were some questions that 3 I would like to have had answered or wanted or desired 4 to have answered. And that was initially what happens 5 in a sponsored clinical trial, what is the process, 6 what occurs, why are you asking me to participate in 7 something that is experimental. And that's very much 8 so the question. And the language that still remains 9 out there is experimental. 10 So there were a lot of questions in my 11 mind as to what occurs, what is the process, why are 12 you desiring me to offer myself to you for research 13 purposes, and what will become of this research? And 14 also, too, what will happen to me? 15 And I think that was one of the primary 16 things that piqued my interest as a research 17 participant, what will happen to me, what will occur 18 in this process. What will allow me to want to say 19 that I will give myself to you and allow you to within 20 the parameters of your study protocol do as is 21 necessary in order for you to achieve your objective 22 and goal? 202 1 That is why I decided to become a study 2 participant. And, just to share with you, my first 3 research study that I participated in was in 1996. 4 And that was Dr. Terri Shapiro at Johns Hopkins. They 5 were actually studying the effects of atovaquone for 6 malaria treatment. And with that, one had to become 7 infected with malaria. So initially right there and 8 then, Tuskegee did come to my mind. 9 And, as Dr. Marrett did speak, I did a 10 brief survey yesterday. And hearing Dr. Marrett 11 speak, it is very interesting what that survey, just 12 real quick, a study population of 20 people who I 13 decided to poll around the Johns Hopkins environment 14 there to see what their attitudes were. 15 Again, I participated in that clinical 16 trial in 1996. And immediately one of the things that 17 was presented to me was being infected with malaria, 18 knowing what malaria is, a person who is in health 19 care. What does that mean for me? Why would I expose 20 myself to what I had heard or knew about as could be 21 potentially a very serious disease and illness? 22 Initially from that, I would have to say 203 1 that it was because of Dr. Shapiro and her research 2 team. Two of those individuals are Ed and Liz, who 3 are members at the Hopkins community. It was because 4 of that research team: one, Dr. Shapiro being able to 5 want to approach her, being able to ask all the 6 questions that I had that were relevant to me as well 7 as other study participants and see that she and other 8 researchers were open to answer the questions and not 9 seeing that there was anything being held from me that 10 allowed me to be able to say that this is then 11 something that I will do. 12 Secondly, at the same time, too, I realize 13 that no, I do not necessarily have a high probability 14 of coming into and contracting malaria. But at the 15 same time, too, I knew that this was potentially 16 something that could help a population of people 17 outside of myself. 18 So that also, too, prompted me to continue 19 in this study, knowing that this information 20 potentially could help a population of people more 21 vast than I could even imagine. 22 And also, too, within that study, that 204 1 study was a study that took place over three months, 2 which I learned a lot of things from that study. But 3 I will have to say initially from that study it was 4 because of the research personnel, their willingness 5 to be open and honest and allow me to ask questions 6 and receive information from them to make an informed 7 decision as to whether or not I would consent that 8 allowed me to continue with that study. And also, 9 too, was the basis for which I determined whether or 10 not I would participate in any other research studies. 11 Secondly, once again, I will tell you that 12 at this time, I was an individual who had graduated 13 from college in the health care field, in research, 14 and would say that I was above average in my knowledge 15 of health care research and the research process. 16 But I will still inform you that Tuskegee 17 still rung in my mind because of what I had been told 18 growing up, what I had learned, and my concerns. That 19 still rung in my mind while I was participating in 20 this research project. 21 Also, too, as I began to participate in 22 research projects, one of the things that I had 205 1 noticed or did notice is that I was one of the few 2 minorities; in particular, one of the few, if not the 3 only, African American, who was participating in 4 research studies. And that sought me to ask why. 5 Particularly at the Johns Hopkins 6 University, a large employer within the city that has 7 a large African American population and a population 8 too which I believe mirrors the African American 9 population in the United States as a whole because you 10 have individuals there who occupy every educational 11 and socioeconomic aspect of the African American 12 community employed at Hopkins, whether they be from 13 someone in environmental services, where no high 14 school degree is required, to those who are 15 researchers, Ph.D.'s, and M.D.'s. 16 So that question was why, too, are not 17 these individuals participating in research projects? 18 So that led me to desire to know why with this 19 information available to you at your disposal are we 20 still not participating? 21 So that led me to want to ask individuals 22 within the Hopkins community as well as personal 206 1 friends. And I will say this. Once individuals, 2 personal friends, a close body of individuals within 3 my church community who knew that I participated in 4 research experiments, that piqued their interest. 5 And, once again, most individuals I will 6 say is that Tuskegee still, as Dr. Marrett said, still 7 rings in the minds of African Americans. Whenever the 8 word "experiment" or "research study" is said, most 9 individuals, not all, the thing that came to mind was 10 Tuskegee. 11 So I think that there is to some degree 12 that it perhaps cannot be used to explain as to why 13 African Americans do not participate in research 14 studies, but I believe that if you are approaching 15 this particular community, that is the first door 16 through which you may have to go for most participants 17 and being able to explain to them and even deal with 18 that issue to allow for one to even broach any other 19 research possibilities. 20 As Dr. Marrett said in her discourse that 21 she cited a number of studies, in my feeble attempt, 22 I will share with you what occurred. Basically I call 207 1 this a survey of attitudes toward sponsored clinical 2 research trials and how knowledge of the Tuskegee 3 syphilis study impacts respondents' future 4 participation in sponsored trials. 5 But also, too, it's how the media's 6 reporting on issues affects general decision-making 7 because that was something that was broached in the 8 meeting that occurred earlier in the year in 9 Baltimore, was how does the media reporting of events 10 but also, too, what happened in 2001, as most of you 11 are aware of, is the young research participant at 12 Hopkins, who, unfortunately, died during one of the 13 research experiments. One, how did that media 14 coverage locally but also to what was written 15 nationally impact individuals? 16 So within this study population, I'll just 17 give you the results. I surveyed 20 individuals. 18 Basically within the 20 individuals, you basically had 19 a 50 percent participation in males and females. The 20 mean age that I found was 45 years of age through our 21 survey, but the range between 18 and 65. 22 I thought it was interesting in regards to 208 1 education -- and, again, this to me is very feeble in 2 regards to what Dr. Marrett put forth, but I found 3 that 50 percent had high school education. Twenty 4 percent had some college. Twenty percent had a 5 Bachelor's degree. And there was ten percent who had 6 graduate degrees, who were either Ph.D.'s or M.D.'s. 7 And how I framed this was that I wanted to 8 make sure that I did not bring up Tuskegee from the 9 outset. My initial question to these individuals was: 10 had they had any participation in a research study? 11 It was interesting that 65 percent had no former 12 participation but 35 percent had had a participation 13 in a research study. 14 And then next I asked the respondents had 15 they heard of the Tuskegee study. And, actually, 80 16 percent had heard of the Tuskegee and 20 percent had 17 not. 18 But of those 20 individuals, for those who 19 did not and had not heard, I factored them out. And 20 that left 16 individuals. And for those who had heard 21 of the Tuskegee experience, my next question, as Dr. 22 Marrett stated, were they able to share with me what 209 1 the specifics of the study were? And of that, 75 2 percent were able to share with me basically what it 3 involved. And I thought that was very interesting. 4 Those who were somewhat knowledgeable, I 5 factored those into the no category. But I thought 6 that was interesting that 75 percent of individuals 7 that I just approached on the street or in the market 8 area were able to tell me basically what the Tuskegee 9 study entailed. 10 And also, too, of those individuals, in 11 seeing and thinking that that was very interesting, I 12 asked whether or not history of the Tuskegee study 13 would affect their future participation in a sponsored 14 research trial. 15 And it was interesting. Fifty-six percent 16 of individuals, regardless of their educational 17 background or socioeconomic background, stated that 18 because of Tuskegee -- and some were adamant, would 19 say that no, because of Tuskegee, I would not 20 participate in a research study or some said that if 21 I did participate in a research study, that rigorous 22 questioning would be put forth to the researchers to 210 1 ascertain exactly what it is that you are trying to do 2 with this research trial that you're asking me to 3 participate in. I thought that was very interesting. 4 And, lastly, of those individuals who 5 responded, it dropped down to 12. I initially in my 6 responses forgot to ask this question to some of the 7 respondents, with regards to the media, because these 8 are things, too, and why I'm saying this, things that 9 affect or had affected my response in regards to or my 10 knowledge in regards to clinical trials and the effect 11 of the media on decision-making. 12 Of those 12, 60 percent of the 13 respondents, I found it interesting that if I put it 14 on a scale of zero to ten, how does the media affect 15 or how much does the media affect? Whether it's 16 positive or negative reporting, how much does that 17 affect your decision-making in anything? 18 I thought it was interesting that in the 19 first zero to 25 percentile, 17 percent of the 20 individuals said that the media did affect them. In 21 the 26 to 50th percentile, it was 33 percent of the 22 respondents. 211 1 In the 51st to 75th percentile, it was 2 actually 42 percent of the individuals said that the 3 media does play quite a large part in their 4 decision-making, whatever it is that they are about to 5 do. And then in the 76 to 100 percentile, it was 8 6 individuals. 7 So I thought that was very interesting 8 from the standpoint that, particularly for myself, as 9 an African American wanting to participate in a 10 clinical trial is not only what information am I aware 11 of, what my experiences are but also, too, what are 12 the outside factors. And naturally, as we know, the 13 media is a graded factor. 14 I think also, too, with these individuals, 15 it shows you that, particularly with the research 16 participant who passes at Hopkins, in the aftermath of 17 that, I did find that a lot of individuals who were 18 aware of my participation in clinical trials 19 questioned me about participating in clinical trials. 20 And, actually, the two things they did 21 bring forward were Tuskegee and then the more recent 22 event that occurred at Hopkins with a research 212 1 participant tended to have individuals more cautious. 2 It did not have me cautious or I was not cautious 3 because these are the things that I learned from 4 participating in a clinical trial. 5 Not so much advertisement for Johns 6 Hopkins, but I know that within the Hopkins community, 7 for those individuals or researchers who are seeking 8 to have individuals respond to their advertisements, 9 that these researchers have ben individuals who have 10 been extremely open. 11 I have not found any researcher who has 12 withheld, to my knowledge, any information. They have 13 gone to lengths to be able to accommodate me with the 14 questions that I have. 15 But also, too, one of the things for 16 myself, not only the researcher, is the study staff. 17 I found that the support staff, those individuals go 18 a long way in making me as a participant or made me as 19 a participant want to continue or want to continue in 20 other research trials. 21 Some of these individuals I have worked 22 with more than one clinical trial, but I know it's 213 1 their dedication to the patient. It's their 2 dedication to making sure that even the researcher 3 stays within the study parameters or their questioning 4 of the researchers. 5 I thought that was very interesting and I 6 would say gives us -- and share with you. And also, 7 too, what I sought to do or have sought to do, if I 8 may divert, is that for the African American 9 population, those individuals whom I could reach out 10 to and I could hopefully influence I've tried to 11 impress upon them of the need for participation of 12 minorities in clinical research trials. 13 Initially with the number of individuals, 14 it's not so much of resistance as it is that they just 15 do not have the information or knowledge of exactly 16 what a clinical trial encompasses. Why are you asking 17 me? And what will this do, not so much from an 18 altruistic standpoint of how will I benefit from it 19 but just what are you wanting to do? What is this 20 for? And I think that is something very important if 21 you are approaching populations, period, but a 22 specific population is what their concerns are. And 214 1 I think that has to be addressed. 2 I also, too, know that for myself, 3 clinical trials have benefitted me from a personal 4 standpoint because I have two experiences from 5 clinical trials where the information that was found 6 out about myself led to from a medical standpoint 7 follow-up on two occasions. 8 And I had a very recent occasion where I 9 participated in a clinical trial that was a 10 neurologist testing a new MRI procedure for carotid 11 artery scanning. 12 And from that -- and I have no problem 13 sharing this with you. I am an individual who is very 14 athletic. I go to the gym four times a week. I do 15 cardio four times a week. I lift weights and have 16 been active in sports all my life. I have a very 17 healthy diet, a very nutritious diet. As a weight 18 lifter, I take no supplements whatsoever and never 19 have. 20 But, yet, from that clinical trial, the 21 neurologist found that there was blockage in my 22 carotid artery, my right carotid artery, which he was 215 1 very interested in. That then led to him following up 2 with my personal physician, which will lead in the 3 next month or so to follow-up studies. 4 So somewhat to the degree as what I have 5 read -- I have not finished the book -- by James 6 Jones, Bad Blood, which I found to be very interesting 7 reading, is what and how do clinical trials benefit 8 me. 9 And I have found out that for myself, a 10 person who is gainfully employed, has health 11 insurance, they, in turn, have supplemented or have 12 been the first line in regards to proactive medical 13 care for me because unless I have participated in 14 these clinical trials, I don't think that these 15 conditions would have ever been noted until possibly 16 somewhere later in my life, where the intervention may 17 not have basically been to my advantage. Let's just 18 say from that standpoint. 19 Again, the things that I would like to 20 share with you are that in regards to participating in 21 clinical trials, I think that for myself being an 22 individual, there was a certain barrier. And there 216 1 was a barrier that I had to overcome, even having 2 information. 3 And that was what are clinical trials, 4 what are the purposes of clinical trials. What is 5 your interest in me in a clinical trial? Particularly 6 specifically when I have seen advertisements that are 7 specifically looking for African Americans, why do you 8 only want African Americans? Why are you only wanting 9 us? So there is a certain level that one has to 10 overcome. 11 And then, secondly, the individuals 12 themselves have to, in essence, be taught, as I had to 13 be taught, what the benefits of clinical trials are, 14 what is the necessity of them. 15 And then, thirdly, I realize that there 16 was a personal benefit that I derive myself from 17 participating in clinical trials. But at the same 18 time, too, once again, the media influence. 19 And that is something that I realize has 20 to be addressed whenever you are going into a 21 particular population, what is that population, just 22 as in Bad Blood and Nurse Eunice Rivers. She was the 217 1 continuity between the researchers and those subjects, 2 that she knew that population. She knew their idioms. 3 She knew their culture. She knew their superstitions 4 almost to a degree. 5 And I think that before you do that, you 6 have to know that about the population because with 7 that, you are able to address it and then be able to 8 possibly -- as with myself because I had to have my 9 superstitions that I had within me addressed in 10 regards to clinical research trials in order for me to 11 be able to from an informed standpoint move forward. 12 So I would like to share those things with you. 13 CHAIRMAN PRENTICE: Thank you. 14 (Applause.) 15 CHAIRMAN PRENTICE: Thank you very much, 16 Darrell, for a very interesting and insightful talk. 17 We would like to now move on to our next 18 speaker, Dr. Jeffrey Henderson. While he is 19 assembling up at the front table, I'll read you a 20 little bit about him. 21 Dr. Henderson is a Lakota and an enrolled 22 member of the Cheyenne River Sioux tribe. After 218 1 receiving his medicine and public health degrees at 2 UC-San Diego and the University of Washington, 3 respectively. He works as a clinician for the Indian 4 Health Service. He is a board-certified internist and 5 epidemiologist. 6 In 1998, Dr. Henderson founded the Black 7 Hill Center for American Indian Health. And i'll tell 8 you a little bit about that. It's a community-based 9 nonprofit organization whose mission is to enhance the 10 wellness of American Indians living on the northern 11 plains through research, service, education. 12 Dr. Henderson is also an assistant 13 professor in American Indian and Alaska Native 14 programs at the University of Colorado at Denver 15 Health Science Center. 16 I'll give you a little bit of information 17 about the Black Hill Center for American Indian 18 Health. It had remarkable success. It's garnered 19 over 9.5 million through 6 NIH peer-reviewed health 20 research grants. And these grants are represented by 21 the largest study ever planned among American Indians 22 and Alaska Natives. 219 1 It goes on to talk about a number of those 2 grants and a number of future initiatives, but, rather 3 than going through that, I will simply turn it over to 4 Dr. Henderson and welcome and thank him for coming to 5 address us. 6 DR. HENDERSON: Thank you very much, Dr. 7 Schwetz and Dr. Prentice and all those who are 8 involved in extending the fine invitation to me. 9 And good afternoon, ladies and gentlemen. 10 It's a pleasure to be here with you today. And, 11 indeed, my name is Jeff Henderson. And in the Lakota 12 language, my Lakota Indian name is Wowokea, which 13 means the helper, or one who helps. 14 And as a Lakota person, we're encouraged 15 to share our Indian name with our audience to whom we 16 speak, but that's not true of every tribe. And so you 17 should not assume in the future that every Native 18 speaker will share his or her Indian name with you. 19 As was noted, I'm the President and CEO of 20 the Black Hills Center for American Indian Health. 21 And, as also noted, this is a community-based 22 nonprofit and research-intensive organization that was 220 1 founded in 1998 but has been a functioning 2 organization with funding only since the Fall of 2001. 3 We actually have just received two new 4 grants that we're releasing press releases on. And we 5 have just reached the 12 and a half million-dollar 6 mark in 3 years with a number of different studies 7 that are noted for you here. 8 The EARTH study is a very large cancer 9 study of cultural, behavioral, dietary, and other risk 10 factors for cancer among American Indians and Alaska 11 Natives. It's the largest study ever planned for and 12 carried out among American Indians and Alaska Natives. 13 This second grant of ours, to be one of 14 the first grantees of the Native American Research 15 Centers for Health Grants Intuitive, a joint 16 initiative from Indian Health Service and NIH, 17 actually was for an individual research project, which 18 was recently concluded, in which we surveyed 1,066 19 tribal college students on the 3 Lakota Sioux tribal 20 colleges in western South Dakota using a vignette 21 methodology to ask them about their participation in 22 health-related studies. 221 1 We had four vignettes, which a vignette, 2 of course, is a hypothetical paragraph. And we had 3 four of those that described four distinct types of 4 research: a focus group study, a cognitive behavioral 5 study, a full-blown genetic study with hair clippings 6 and fingernail clippings, and a randomized clinical 7 trial. The results of that study are being published 8 in a new sage book, publication, that is due out this 9 fall. 10 The third study that we received funding 11 for is the SAND study, which stands for Stop 12 Atherosclerosis Among Natives with Diabetes, study. 13 This is the first ever randomized clinical trial in 14 Indian country outside of child and infant vaccine 15 trials and cognitive-behavioral interventions. This 16 is the first, you know, truly full-on randomized 17 clinical trial from Heart, Lung, and Blood to try to 18 prevent or reduce cardiovascular disease among 19 American Indians 40 years and older with Type II 20 diabetes. 21 We have several other grants as well. And 22 those in the shaded purple are grants that we have 222 1 worked up and have submitted in our appendix. In 2 fact, we're ready to report the receipt of this grant 3 here, which for the very first time here in the North 4 America, we will be conducting research in direct 5 partnership with a group of traditional healers. 6 You know, the Native healing traditions of 7 Native peoples in North America and to some extent in 8 Central and South America, too, have long fascinated 9 anthropologists and ethnographers and other social 10 scientists, who have not hesitated to write down what 11 they saw, what they heard, or what their 12 interpretation of what they were seeing or hearing 13 was, usually getting it wrong. And this will be the 14 very first time that NIH anyway is funding such a 15 study. 16 You can appreciate the sensitivities that 17 might go along with plans for a study of that kind. 18 Perhaps I'll get a chance to say a little bit more 19 about it. 20 Well, what is the upshot to all of this? 21 In the last 18 months, we have consented in toward 22 various research studies over 4,000 of our people. 223 1 And in the next 18 months, we plan to consent to 2 another 3,000. 3 So these are not small focus groups. 4 These are some serious undertakings. We have three 5 groups of eight researchers on the ground on five 6 reservations around the country right now. 7 Well, let's take a look at a few of them. 8 The EARTH study, as I mentioned; the cancer study. 9 This is actually a feasibility baseline study for what 10 is planned as a long-term longitudinal cord study of 11 risk factors for cancer. 12 We are joined with two partners in this 13 research. And in this baseline feasibility study, the 14 three partners intend to recruit 16,000 of our people, 15 Eclipsian by far the largest previous study that has 16 been undertaken. And our intention in doing so is to 17 establish the methodologies that will ultimately be 18 used to recruit that cohort up and over 80,000 19 individuals for long-term follow-up. 20 In our part of the study, we work with 21 three tribes: the Shine River Sioux tribe and the 22 Oglala Sioux tribe, which are both Lakota Sioux tribes 224 1 in western South Dakota; and the Salt River and Gila 2 River Pimamiracopa communities south of Phoenix that 3 have been in the news quite a bit recently and which 4 you may more popularly know as the site of the world's 5 highest prevalence of Type II diabetes. 6 We are doing a few things that are unique 7 in this study that our other two partners are not 8 doing. And one of the things -- and this will bear on 9 a comment I will make in a little bit. But one of 10 those is we used some of our grant funds, even though 11 this is a cancer study, to purchase these hologic 12 Sahara heel ultrasound machines for the determination 13 of peripheral bone density measurements on all of our 14 people. 15 The SAND study is this randomized clinical 16 trial to try to reduce or prevent heart disease 17 through very aggressive risk factor lowering, 18 principally keen on mean systolic blood pressure and 19 LDL, or the so-called bad cholesterol. 20 We are a subcontractor on that study with 21 the only clinical site in the Northern Plains at Sioux 22 San. Sioux San is short for Sioux sanitorium. It is 225 1 a former tuberculosis hospital in Rapid City, which 2 was started as a tuberculosis sanitorium in 1929 and 3 functioned as a TB sanitorium all the way through 4 1969, when at which time it was converted to a general 5 acute care hospital and clinics. 6 We have very aggressive goals on this 7 study. In the aggressively treated group, the mean 8 average systolic blood pressure to be achieved is 115, 9 very low, not the lowest that is attempted to have 10 been targeted in such a clinical trial but as of the 11 18-month midpoint in our study, we, in fact, have 12 achieved a mean systolic pressure across our 13 aggressively treated individuals less than 115. It's 14 the lowest mean systolic pressure that has ever been 15 achieved in any randomized clinical trial in any 16 population. 17 Now, think to yourselves about the 18 likelihood that any of our or many of our 19 participants, American Indian, 40 years and older, 20 with Type II diabetes with mean hemoglobin H1aC of 21 about 9.5 or 10 have seen systolic pressure in 22 themselves of 115 in 10 years, 15 years. 226 1 I say that by way of saying this by far is 2 the most difficult goal for us to achieve. And we're 3 running into situations now where for the very first 4 time in a randomized clinical trial, our people are 5 having serious adverse events. Fortunately, we have 6 not had any in our particular center that are directly 7 attributable to participation in the study, but there 8 have been at three of the other clinical trial 9 centers. This is the very first time. 10 You can appreciate this. This is sort of 11 a watershed moment for the population because, as is 12 the case with many randomized clinical trials, there 13 can be some serious adverse events. And it's 14 important that our participants know and understand 15 what those risks might be and accept to be exposed to 16 those risks. A few more details about the SAND study 17 for those of you who are inclined. 18 Well, so what has been our experience 19 conducting this research? It's been very interesting, 20 to be sure. And through this experience, we have 21 certainly learned a few caveats. 22 What I might also do, though, is to set 227 1 the stage for the few slides that I'll show next. You 2 know, many of you are aware, though it's not taught 3 very well in our schools at all what the plight of 4 tribal nations has been in this country. 5 And for us Sioux particularly, the events 6 of December 29th of 1890 in Wounded Knee, South Dakota 7 are only four generations ago. And, in fact, there's 8 a vibrant and alive oral history that surrounds the 9 events around Wounded Knee and the massacre of 276 or 10 slightly more largely unarmed Lakota Sioux women, 11 infants, and children and a few very sick chiefs, 12 including our Chief Bigfoot, who was stricken with 13 pneumonia at the time. And, of course, 18 of those 14 cavalry members received the Congressional Medal of 15 Honor. 16 And some of you may have seen the 17 portraits of the mass burial grave at Wounded Knee on 18 an incredibly frigid, cold January 1st, New Year's Day 19 of 1891, when gathered around, all proud, perched on 20 the butt ends of their shovels or the cavalry members, 21 and Chief Bigfoot is lying on top of the pile, his 22 left foot frozen, outstretched parallel to the ground, 228 1 as he is on top of that pile. 2 Many of those people have those pictures. 3 I have those pictures myself in my collection of 4 pictures. And so it, in fact, as difficult for us to 5 divorce as it is concerns around research per se from 6 larger concerns as relate to the federal-Indian 7 relations through time and what we know to be some of 8 the practices that have been carried out on the people 9 -- and I say that both as a tribal member myself and 10 also as a researcher who is conducting a lot of 11 research with our people -- if there's going to be a 12 distrust of the government or particularly a distrust 13 because they know that the government is funding the 14 research, it's as likely that hesitations or 15 reluctance to participate will depend on these 16 non-research events in history than distinct research 17 events. 18 Even though there have been some discrete 19 research events that our people have been subjected to 20 through time, there were the I-131-radiolabeled iodine 21 studies that were conducted among Alaska Natives in 22 the 1950s, before I-131 would become a standard of 229 1 care for ameliorating one's thyroid if you were 2 hyperthyroid. 3 There was the Barrow alcohol study in the 4 '70s when a distinguished team of East Coast 5 researchers hearing about a tremendous alcohol and 6 alcoholism problem in Barrow, which was a municipality 7 in northern Alaska went there and spent a couple of 8 weeks surveying people, looking at the detox records 9 and other social records and interviewing a few 10 people, went back to their distinguished East Coast 11 institution and wrote up their research paper, didn't 12 vet it with the tribe or the Native peoples at all. 13 And it was published on the front page of the New York 14 Times with sensational coverage all around the 15 country. 16 To make a long story short, as a result, 17 Moody's, the bond rating service, dropped the 18 municipality of Barrow's bond status from A to junk 19 status literally overnight, subsequently costing the 20 community millions of dollars in missed opportunities 21 for capital in subsequent years, so with dramatic 22 results to that community. 230 1 Many of our American Indian, Alaska Native 2 women, too, joined women of all different types of 3 color in the 1970s through relaxed laws around 4 reproductive rights in undergoing lengthy and 5 well-documented cases of coerced sterilization. 6 In my clinical practice, you know, it's 7 not uncommon at all for me to run into 50-year-old or 8 so women, still significantly grieving our their total 9 abdominal hysterectomy that they had had at some point 10 in the '70s, either before they had had a chance to 11 have any children at all or after their very first 12 pregnancy, many of which at the time were delivered by 13 Cesarean. And when the woman became postpartum, only 14 then did she realize that, in fact, she had had all of 15 her birthing apparatus removed. 16 There was early pre-FDA approval use of 17 Depo-Provera in Norplant in the 1980s among women in 18 our population. And then we have the present very 19 well-publicized situation right now with Havasupai. 20 How many of you are familiar with what the issues are 21 with Havasupai? 22 Havasupai, a little tribe on the bottom of 231 1 the Grand Canyon, gave their permission for 2 researchers of a Southwestern institution to conduct 3 some diabetes-related research, seemingly unaware, at 4 least as far as we can tell unaware, that in the 5 evening after hours, these researchers or agents for 6 the researchers were in the medical clinic at that 7 tribe after hours, in fact, documenting the prevalence 8 of schizophrenia in the population. 9 And blood samples that they had given up 10 to these researchers, also ostensibly to be used to 11 look at diabetes, were sent off here and there around 12 the world, both to underscore this schizophrenia 13 research as well as to one group that was using their 14 samples to explore the peopling of the Americas, which 15 is a real popular research track. 16 Well, what should you know or what would 17 I wish for this group to know about conducting 18 research among our people? The first is that at last 19 count with the Bureau of Indian Affairs, there are 20 over 565 discrete federally recognized tribes, 21 Indians, in this country, over 565. 22 They are domestic, for legal purposes 232 1 considered to be domestic dependent nations with 2 sovereignty. And this last phrase, "with 3 sovereignty," is a course of issues to no end over 4 jurisdictional issues between tribes; their local 5 municipalities; counties; states; and, indeed, the 6 federal government. 7 What I would wish for NIH to know is that 8 this has significant implications for the sweeping 9 edict through NIH for this data sharing off of data 10 coming off of these various studies. 11 The other issue of working with tribal 12 nations is that there are very unique types and levels 13 of approval, which vary by tribe. There's no one shoe 14 fits all when you as a researcher are attempting to 15 access a tribal community or a reservation to conduct 16 research. 17 You need to find out what the normal 18 approval process is. It's very often different. And 19 in almost every case, those 565 federally recognized 20 tribes and many state-only recognized tribes hold unto 21 themselves the ability to approve or disapprove of 22 your research project at a group level at the tribal 233 1 council level before you ever get a chance to ask an 2 individual whether he or she would like to participate 3 in that research. 4 So although theoretically and 5 hypothetically, there are bioethicists all over the 6 country who are advocating for us to go search out 7 some type of group consent process for research, this 8 is very much a reality on the ground in many 9 reservation settings. 10 As a researcher, one of the most 11 exasperating things that I do is deal with multiple 12 IRBs. Not only do an increasing number of tribes in 13 the country have their own IRBs right now, but, of 14 course, these tribes also exist -- I could have shown 15 a map, but these tribes also exist with respect to 16 their Indian Health Service health care system in one 17 of 12 well-circumscribed regions, administrative 18 regions, in the country, which correspond also to the 19 Bureau of Indian Affairs regions in the country. And 20 each of those areas have their own IRB. 21 And where you propose in your research at 22 all to utilize or otherwise conduct your research on 234 1 Indian Health Service property or in Indian Health 2 Service facilities or use Indian Health Service data, 3 you need to send your project through one of those 4 IRBs. 5 Now, if you're a member of an academic 6 institution, you also need to send your proposal 7 through your academic institution's IRB. And then, 8 finally, when it's functioning well, the Indian Health 9 Service has a national IRB that according to some line 10 of reasoning that I have personally not been able to 11 understand, some procedures, particularly where they 12 cross state lines and may cross the area, cross tribes 13 that are across different areas within the Indian 14 Health Service, we need to send our proposals to the 15 national IHS IRB. So you may have the tribes' IRB, 16 the local Indian Health Service IRB, your 17 institution's IRB, and the national Indian Health 18 Service IRB. 19 That is not the end of it. Recently one 20 of our tribes that we work with in western South 21 Dakota, one of the Lakota Sioux tribes exerting its 22 sovereignty, said, "Enough of this business. Where 235 1 the IRB that oversees your work has to first see a 2 letter of approval from us before they will approve 3 the study, we want to exactly reverse the table. The 4 IRB approves it first. Then we'll approve it." 5 Well, it took me about six months to get 6 the IRB and that tribe together to work it out amongst 7 themselves since here I, as the researcher, was caught 8 up in the middle of what I agreed the tribe should 9 have the right to do that. 10 But the IRB had never had a tribe tell 11 them that before. And, you know, you can appreciate 12 that probably many calls were made here to Washington, 13 I suppose. What should we do, you know? So there is 14 that twist on it, too. 15 Very different demographics in our 16 population. The 2000 census stated almost 17 miraculously there were about 4.1 million American 18 Indians suddenly in the country from 2.2 just 10 years 19 ago. But, of course, in the 2000 census, for the 20 first time you could claim multiple racial or ethnic 21 composition. 22 And of those 4.1 million American Indians, 236 1 wholly 50 percent are 18 years and younger, very young 2 population. And, for better or for worse, about 1.8 3 million of those 4.1 million American Indians 4 according to the census are beneficiaries of the 5 Department of Health and Human Services' very own 6 Public Health Service Indian Health Service, of which 7 I have been a provider for over 5 years. 8 Many of our reservation settings 9 frequently lack many of the typical resources that 10 researchers in other areas, particularly in 11 metropolitan areas, can reach out to partner with, to 12 conduct their research, either through or along with 13 or potentially even receive funding from many of those 14 types of partners are, frankly, not available in our 15 reservation communities. 16 Now, many of our tribes in our area do 17 have tribal colleges, but a universal feature of most 18 of those tribal colleges is very little, if no, 19 science exposure at all. They're mainly nursing, 20 mainly smaller business administration, and mostly 21 associate degrees, not very many four-year-degreed 22 institutions. And our people have such pressing needs 237 1 that health research as a topic just falls well down 2 the priority list. 3 So what can we do? The biggest thing that 4 we can do is to simply be there. And this is a 5 concept that works in many of our tribal communities. 6 I can sum this up as the following. 7 I was in southeastern South Dakota the 8 last several days on the Yanktoni Sioux reservations 9 in southern Charles Mix County in South Dakota. And 10 I had a non-Native individual who had come into town 11 for the same conference I was at say, "You know, we 12 tried to work with these people on research. We must 13 have showed up here eight different times, said that 14 we would be on the agenda for that meeting. And we 15 sat there on our hands all day. They never brought us 16 in front of the tribal council on it must have been 17 eight or ten different times. We just finally got so 18 fed up we just went home. And we have never been 19 back." 20 Well, we've done the same, but I've 21 understood what this is about. I have the advantage 22 of being a tribal member, right? You're being tested 238 1 when you're sitting there. 2 You know, how haughty and full of 3 arrogance and hubris are you going to be sitting there 4 in your uncomfortable folding chair for eight hours 5 waiting for that tribal council to bring you up in 6 front of them while they're micromanaging every little 7 tiny employment situation with every tribal employee 8 worker and approving the next round of student 9 scholarships or whatnot when you have got your 10 important research project that you want to get 11 approval for? 12 But if you sit there, if you show you're 13 respectful, if in breaks you talk to people, if you 14 just let people know that you consider your time all 15 that very valuable, that you're not willing to do 16 that, if this is really something that you want to do 17 and you be there, that is a very important topic. 18 A few more things as I know my time is 19 about up. I mentioned to you we secured these hologic 20 Sahara ultrasound machines for the peripheral 21 determination of bone density. Well, it has really 22 not much to do with cancer. But what it is is a 239 1 diagnostic service that is not available. And it's 2 not paid for by the Indian Health Service. 3 And so the fact that we're able to provide 4 that for people who will never get the IHS to refer 5 them for this unless they're elderly and fall down and 6 break their hip or break their femur is a real plus. 7 Many people we have been told come to our study, 8 especially middle-aged individuals, to get their bone 9 density checked. 10 We employ many tribal people. We try to 11 employ tribal members for our interviewers, our 12 recruiters, data collectors, chart abstracters, et 13 cetera. 14 Well, thank you very much for this 15 opportunity. It's been a pleasure. 16 (Applause.). 17 CHAIRMAN PRENTICE: Thank you very much, 18 Dr. Henderson. 19 Would the panelists please assemble? 20 (Pause.) 21 CHAIRMAN PRENTICE: Okay. This summer 22 OHRP staff, including Dr. Schwetz and myself, had the 240 1 pleasure and the honor of participating in some 2 conferences devoted to Native Americans and Alaska 3 Natives. And they were held, as you know, Dr. 4 Henderson, in North Dakota and South Dakota, the most 5 recent one being in Rapid City. 6 I want to tell you a little bit of an 7 anecdote. Please correct me if I've got this wrong. 8 I was conducting a breakout session that had a number 9 of American Indians participating. And we were 10 talking about how you present proposals for research 11 that involve American Indians. And, of course, 12 there's a tribal council you have to go through, and 13 there's also the elders sometimes. 14 And they were talking about, well, you 15 know, you go to the reservation and you get an 16 appointment. And you wait around. And maybe you get 17 to see the elders that day. Maybe you don't. But if 18 you do, you bring them tobacco. And you don't talk 19 about what you want to do. You talk about whatever 20 they want to talk about. And when they're ready to 21 talk to you about the research, then you can talk 22 about it. 241 1 I found that a fascinating education, 2 really, because, you know, that's not the way we 3 normally do research involving non-American Indians. 4 So your story was reminiscent of that experience that 5 I had in learning about this way of doing research. 6 I also want to make one comment with 7 regard to the initiatives that are going on in the 8 American Indian, Native Alaskan community. And that 9 is to have IRBs set up on reservations so that when a 10 researcher wants to conduct research on a given 11 reservation, they not only go through their university 12 IRB if they have one. 13 They go through the tribal council. They 14 go through an IRB on the reservation. And then if 15 they involve Indian Health Service facilities, as you 16 mentioned, they probably have to go through the Indian 17 Health Service IRB. So obviously the approval route 18 is rather onerous. 19 But these conferences were designed to 20 help individuals set up those kinds of IRBs. So there 21 were three days of intensive training. That was the 22 last conference that we were at in teaching people how 242 1 to set up an IRB from A to Z. 2 That said, Cora and Darrell mentioned 3 Tuskegee a number of times, the Tuskegee legacy, the 4 Tuskegee effect. And, of course, you talked about 5 some of the unethical research that involved your 6 people, some as recently as 2004, the Havasupai. 7 Is there a similar effect among American 8 Indians and Alaska Natives where they distrust 9 biomedical research, particularly perhaps the white 10 research establishment? 11 DR. HENDERSON: Yes, there is. You know, 12 we consented, thousands of our people, through their 13 EARTH study and consent 20 to 30 a day Monday through 14 Friday presently. A surprising number of those ask 15 about the situation at Havasupai, having read 16 something about it. 17 Many of our reservations have printed 18 versions of the Moccasin Telegraph, sort of gossipy, 19 you know, gossipy, freewheeling sort of community 20 publications that a story like this will be picked up 21 and various things made out of it. 22 Also, a surprising number of American 243 1 Indians, particularly middle-aged and older, are also 2 aware of Tuskegee and are able to mention Tuskegee 3 specifically. In fact, in a few of our studies, which 4 involve recruiting older individuals, elderly 5 individuals, they will be more likely to even let us 6 know they are familiar with Tuskegee than the 7 Havasupai situation. 8 CHAIRMAN PRENTICE: Okay. That leads me 9 to my next question. It would seem to me that the 10 system of oversight that you are developing should 11 help dissipate some of that distrust, I would think, 12 because it's awfully hard for a researcher to get 13 access to American Indians or Alaska Native 14 populations without going through a rather onerous 15 approval process. Would that not help to dispel some 16 of this distrust? 17 DR. HENDERSON: I hope so, and I think so. 18 We realize that all of our studies bear the potential 19 to address and ferret out some of those reasons for 20 reluctance to participate. I think we're doing that. 21 The real upshot will be at the end of our 22 projects, though, when we'll do something that has 244 1 rarely been done. And that is to spend some number of 2 days, weeks, or months in the communities mirroring 3 back the information, the data that we have gathered 4 to the communities, assigning our staff members to sit 5 down with their tribal health departments, to go over 6 a data set that we'll prepare for them to see if more 7 mileage can be gotten out of that data for any 8 planning or research purposes that the tribe itself 9 may have because the tribes are always writing 10 proposals not to NIH usually but to other aspects of 11 the government and other private foundations as well. 12 And the information we obtain is some of 13 the best information we can be pretty sure, some of 14 the very best information that's been obtained on 15 these tribal members. And so we go to no end to share 16 that with our participating tribes. 17 CHAIRMAN PRENTICE: Okay. One more 18 question for Cora and Darrell before I turn over the 19 microphone to the rest of our SACHRP members. 20 Cora, you mentioned overcoming barriers as 21 a consequence of the Tuskegee legacy. In the African 22 American community, you don't have a similar system. 245 1 I mean, you don't have reservations, obviously. And 2 you don't have tribal IRBs. So there's not that kind 3 of oversight that Jeff mentioned to perhaps overcome 4 some of the distrust. 5 So you also talked about overcoming 6 barriers through targeting education and economics, as 7 opposed to trying to target people based upon race. 8 What are institutions doing across the 9 United States to try to overcome these barriers and 10 enroll more African Americans in research for their 11 benefit? Are there some leading institutions that are 12 really getting out and trying to correct this problem? 13 DR. MARRETT: I thought this was probably 14 going to be a part of the response to your earlier 15 question. And that is, I think about the Institute of 16 Medicine's report, where it talks about the system of 17 protections, implying that it's not just whether you 18 have an oversight group working on IRBs, but it's a 19 question of all of the things that are going on. 20 If there, for example, as I was 21 suggesting, is something less than adequate medical 22 care, that carries over. If there is something less 246 1 than trust with the educational system, that carries 2 over, too. So to that extent, it is very difficult to 3 separate out and think that the problems get solved 4 just by working on the system of protections. 5 In that sense, then, I think that there 6 are lots of matters that come into play. And that's 7 why I like going back to that whole IOM approach that 8 says you've got to try to work through where everybody 9 is thinking of the ways in which their activities come 10 to bear. 11 Now, Darrell will give you a more specific 12 example, but I was thinking of it when you gave the 13 examples of the visits to South Dakota, wondering what 14 were the lessons that those who went to South Dakota 15 -- what did you pick up because it's not just a matter 16 of the tribal IRBs being able to handle the situation, 17 but it's what the lessons are that are taken into any 18 number of settings. 19 So yes, there are some things that are 20 going on, but I will leave it to Darrell to be more 21 specific there. 22 MR. FORNEY: Listening to your question 247 1 and listening to Dr. Henderson's response in regards 2 to the tribal IRBs and when you did say in regards to 3 the African American population, perhaps there's not 4 that formal body, I thought quickly and to share with 5 you that there really is that formal body. Perhaps it 6 may be informal, but it is there. 7 And I will give you three examples and 8 very much within the African American community, the 9 church. That is almost tantamount and paramount to 10 the tribal IRB. And, secondly, you have such 11 institutions such as fraternal institutions, societies 12 and lodges; and, thirdly, the family with the African 13 American community. 14 I think those three areas, particularly if 15 you're talking about dissemination of information or 16 trying to reach a population, are the three vehicles 17 by far that African Americans perhaps have some 18 involvement with, either individually, personally, or 19 within their structure; and very much so the church, 20 particularly thinking of the President, if I may say, 21 with his faith-based initiative, things that are out 22 there. 248 1 And even at Johns Hopkins, one of the 2 researchers on my floor -- I'm not going to call their 3 name, but in order to reach the African American 4 populations, they have along with the churches in the 5 Baltimore area, that has been the vehicle through 6 which they have targeted or for their target 7 population have worked with. 8 And I think those are things that you have 9 to know, particularly with the African American 10 community, if I may say, just as with Dr. Henderson 11 from a Native American standpoint are those informal 12 institutions that one would have to consider if you 13 are trying to reach this population for any reason. 14 CHAIRMAN PRENTICE: So one final comment. 15 It would seem to me that a reasonable initiative would 16 be for an institution to develop programs, 17 community-based programs, where they would go out to 18 the community and talk about research, perhaps 19 research projects that are available, but they would 20 also bring back results of research projects back to 21 the community and give them the results. 22 So you kind of have it at the front end, 249 1 and you have it at the back end. Would that be a 2 reasonable approach? 3 DR. MARRETT: Yes. I would say that is a 4 very reasonable approach because it is a fact that a 5 lot of African American communities might not seem to 6 be all that structured. 7 But people have learned that if you are 8 going to go in and do research, you had better check 9 with some of the elders. You had better make sure 10 that a number of people know what is going on and can 11 interpret what is taking place. But often what 12 doesn't always happen is to do it on the other end. 13 Once there have been some results or 14 whether there are results with keeping people 15 informed, it's only really been let's do it in the 16 initial stages. But it's important, we're suggesting, 17 for that entire time to stay in fold, even if it 18 doesn't seem like a highly structured community. 19 DR. HENDERSON: As an example of that, in 20 our randomized clinical trial, the SAND study at the 21 12-month mark after the first 12 months of a 3-year 22 follow-up period, we convened a community dinner on a 250 1 Saturday afternoon, with invitations sent out to all 2 of our 138 participants and their families. 3 And with respect to the EARTH cancer study 4 that is out on these three reservations, every summer 5 we sponsor large powwow gatherings and sponsor the 6 dinner feeds for the gatherings and have our staff, 7 the staff of that study, serve the soup and prepare 8 the buffalo. And we have our very large banners 9 flying and really help people to see that we really 10 are a part of this community, so much so that we're 11 willing to invest time and energy into it. 12 MR. FORNEY: There is one thing I would 13 like to say. And I heard it mentioned, I believe Dr. 14 Prentice or Dr. Schwetz. That was in regards to 15 legacies. I think that's something personally I 16 believe that has to be thought about or looked at. 17 Legacies are what they are. They're 18 legacies, whether it is a positive or a negative 19 legacy. I think of quickly in Britain, Lord Nelson's 20 victory at the Battle of Trafalgar. That's a legacy 21 in regards to naval history. 22 But I think in regards to Tuskegee, that 251 1 is a legacy. That is a legacy that will endure now, 2 as it has for the past 70-plus years from when the 3 study started, and will endure perhaps another 100 4 years if we're still on this Earth, if I may say that. 5 So legacies will always have to be 6 contended with, but I believe it is how the present 7 responds to the legacy with its current knowledge that 8 may impact any future success. 9 I believe with a legacy such as Tuskegee, 10 one has to be absolutely frank, honest in regards to 11 that legacy, what it is, what occurred, why it 12 occurred, and now be able to at the present with 13 current knowledge address the historical context of 14 that legacy with how now to move forward. I think 15 that is something that perhaps is not necessarily done 16 because of the fear, because of the fear that yes, it 17 was Tuskegee. 18 Yes, this was done. Individuals were 19 recruited into a study. These individuals were not 20 treated, intentionally not treated. That's a legacy 21 that occurred. And that's over a 50-year time period, 22 enough where a legacy can be established. 252 1 But it's now with that body of knowledge 2 to say currently, this is what we desire to do, what 3 we will do and ensure in order for potentially 4 individuals, once again, as Dr. Henderson, those 5 tribal individuals, the churches, the fraternal and 6 social organizations, and even the family in large, 7 because when I started to participate in research 8 experiments and when -- my father had been deceased at 9 this time, but when my mother became aware of this, it 10 was an immediate sense of reservation that persisted 11 or permeated throughout the family. 12 And I had to overcome and get through some 13 even family resistance to my participation in research 14 studies, though it was my decision. Yet, they voiced 15 enough reservations regarding these things that I had 16 to address to them in order for them to understand 17 what I was doing. 18 CHAIRMAN PRENTICE: Floor is open. Ada 19 Sue? 20 MEMBER SELWITZ: I want to thank you. I 21 thought the presentations were excellent and very 22 enlightening. 253 1 I want to direct my question to Dr. 2 Henderson. I did have an opportunity, although, 3 unfortunately, limited to have some involvement with 4 Native Alaskans. And I learned a lot in the process 5 of the kinds of challenges that are faced in doing 6 research. 7 Shifting a bit from recruitment but 8 shifting to maybe the challenges of actually being 9 able to implement a protocol, what I would like to ask 10 you is you have so many layers of review. 11 I mean, that was one of the things that 12 amazed me, I mean, the multiple layers of review. I 13 thought you were very kind in your description and 14 didn't express the frustration that I think I would 15 perhaps feel. 16 And so my question to you is, is there 17 value-added in there or is it a situation where, in 18 fact, there are not strengthening protections for your 19 subjects and it is just unnecessary bureaucracy? I'd 20 like to hear your reaction from a research 21 perspective. And if, in fact, it's the latter, I'd 22 like to hear if you had any suggestions. 254 1 How do we ensure subjects are protected 2 without overburdening the researcher in the process? 3 DR. HENDERSON: I don't think there is a 4 great deal of value added in the multiple review 5 layer, but there is some. The principal value that I 6 see is that more people are made aware of what it is 7 that we intend to do. That is always better, to be 8 more inclusive of people knowing about what you're 9 doing than exclusive about it. And so in that 10 respect, I think it does add a little bit of value. 11 I have long been of the opinion and I have 12 told our project officers and members of study 13 sections that I've sat on the same thing. The one 14 thing that NIH could do to significantly increase the 15 protections of Native participants in research would 16 be to require that applicants for research grants both 17 identify and have approval in hand from the tribes 18 that they say they are going to work with because the 19 thing that undermines our work the absolute most is 20 situations where researchers from generally prominent 21 institutions come out onto reservations with their 22 grant money in hand, their funded research project not 255 1 ever having prospectively identified the Native group 2 that they're going to work with, and thereby use it as 3 a shoehorn to leverage that tribe's buy-in because, 4 let's face it, five of the top ten poorest counties in 5 America are reservation counties, including the first, 6 fourth, fifth, seventh, and ninth counties in America. 7 These are some incredibly impoverished area. 8 And for a researcher to tell the tribal 9 health department of the tribe, you know, "We'll give 10 you a $50,000 subcontract" or whatever can carry a lot 11 of weight. But, of course, what we can also probably 12 also appreciate is that one of the potential places 13 where a study can go wrong is a study that was 14 developed in a generic sense, not meant to fit any 15 specific cultural group, and then is shopped around 16 after funding is gotten. And that happens all the 17 time, even today. 18 And where I have had people come up to me, 19 you know, and run me up one side and down the other 20 over some of these things, it's not been our group but 21 other groups. And in our area, in our very same 22 geographic area, frankly, in western South Dakota, 256 1 it's getting crowded. It's getting crowded out there. 2 And every time I am on the reservation and 3 manage to bump into my relatives or a council person 4 in the hallway or whatever, almost always they'll tell 5 me, you know, "Say, did you hear about, you know, such 6 and such people from over there wanted to do some 7 crazy thing"? 8 I guess they feel like I should like be on 9 missions about what everybody is planning, you know. 10 Of course, I'm not. And so I am always just as 11 surprised as they are. 12 And then I go to the tribal health 13 director. This is the thing on the tribal side I have 14 been advocating for so long. There should be like a 15 research czar. On every reservation, there should be 16 one person who knows everything that is going on with 17 respect to health-related research on the 18 reservations. And that generally should be the tribal 19 health administrator. And almost invariably there is 20 not that person on a reservation. 21 I can always surprise the tribal health 22 director by saying, "Say, you know, Jamie, I heard 257 1 that XYZ University is doing this water sampling down 2 there." 3 "Really? I didn't hear, no." So they're 4 not really aware of what is going on. So, again, 5 that's a way for me to say, you know, you can really 6 appreciate the potential for harm that's out there. 7 And we see it. The tribe now, several of 8 the tribes we work closest with have begun to vet some 9 proposals by other institutions by us, I mean, looking 10 to us to say, "Look at this. How does this look to 11 you? This doesn't make sense to us or does this make 12 sense?" because they, frankly, don't have -- perhaps 13 they, frankly, both don't have in there themselves nor 14 maybe do they trust the layers of the review process 15 to kind of do that ferreting out for them. 16 I'm very reluctant to do that, you know, 17 as you can appreciate. 18 DR. MARRETT: It is just with reference to 19 the question, I know this group, SACHRP, as has been 20 true of every recent group, is concerned with our 21 processes, reducing the levels of efficiency and at 22 the same time not enhanced protection of participants. 258 1 I think what has been running through this 2 panel at least is a concern about the existing levels 3 of trust or distrust. And when there isn't a level of 4 trust, this isn't just about how are you protecting 5 the participants. It's how are you securing some 6 sense that there won't be some other violations that 7 will take place. 8 So it adds another layer, I think. And 9 that's why it's not that simple nearly to say, "Let's 10 try to figure out the most efficient way for 11 operating." That's what takes a while to build. 12 MR. FORNEY: And just to add to that, I 13 think also, too, as well, initially what I read from 14 Mr. Jones book Bad Blood and what some of the 15 participants with the Tuskegee study were questioning 16 in regards to the process and wondering why we had to 17 go through these things, realizing that the 18 researchers were thinking from their perspective but, 19 yet, to understand the participants and how they are 20 viewing this as well deems why you may have to do 21 things. 22 But as they were speaking, I was thinking, 259 1 even with the brief survey that I did yesterday, which 2 I consider very small and very rudimentary, when you 3 look at the people, 50 percent of the people I 4 approached -- and, again, all African Americans. I'm 5 interested to see how this mirrors the African 6 American population as a whole within U.S. 7 But, again, you have to compare these 8 individuals as of yesterday versus what happened in 9 1992, at the initiation of the Tuskegee study. The 10 African American population, these individuals in my 11 study, 50 percent at least had a high school 12 education. 13 So you're talking about a population of 14 people for the most part now from an educational and 15 socioeconomic standpoint are much markedly improved 16 than was 70 years ago. But still, after 70 years, 17 with socioeconomic and educational gains, the thing 18 that you may be encountering is not because of a 19 person's lack of knowledge or ability to process or 20 understand informed consent and to be able to go from 21 A to B quickly and the reason why you may have to have 22 C and D is because you're still dealing with 260 1 historical contexts, legacies, and also, too, just 2 attitudes that are built in. 3 I even have a coworker who is in the 4 process of completing her doctoral history in the 5 specialization of the transatlantic slave trade and 6 the history of medicine and because of her knowledge 7 of these things, the Tuskegee study and ability to 8 have done research, adamant to not participate in 9 research studies, a person with a graduate degree but 10 has stated, "No, I will not participate in any type of 11 research studies because of Tuskegee and the things 12 that I have learned." 13 So there is some value when you have to 14 consider these things that are not quantitative things 15 but qualitative things that you have to assess and 16 consider the process. 17 CHAIRMAN PRENTICE: Felix? 18 MEMBER WEINER: I just wanted to follow up 19 on the concept of trust. We heard this morning from 20 -- Mrs. Wachtel spoke about trust as well and talked 21 about the violation of trust and talked about the 22 essential nature of the initial bond between the 261 1 patient or patient's family in this instance and the 2 treating physician; of course, the conflict between 3 the researcher and the treating physician and what 4 those dual obligations represent. 5 There is that level of trust, which is the 6 sine qua non. But then there is also the level of 7 trust in government decisions and oversight. I think 8 we have to keep both in mind all the time as we have 9 these discussions and figure out ways as we go through 10 this to address both of these. 11 I guess that brings me to my question, 12 which is do you have the sense that in either 13 community, that there is a level of distrust with 14 respect to face-to-face medical care, even under dire 15 conditions, where clinical trials may be exactly what 16 is called for, but they are -- because they are 17 research, they are no longer acceptable. 18 Even in the face-to-face situation, not in 19 the abstract, I choose not to participate in research. 20 But when the rubber meets the road, is it still the 21 same? 22 DR. MARRETT: I think you asked the 262 1 question because you have got to answer it, like your 2 response to it. Clearly when it comes to getting to 3 know and having that very close relationship, there 4 isn't that kind of -- there's not as much of that 5 distrust, but I think the point you were making is 6 it's not enough to create profound trust at the 7 interpersonal level. 8 That's fine. But if it's a set of 9 processes, if it's a structure that can be 10 problematic, then that has got to be addressed, too. 11 What was the statement that the Soviet leader used to 12 use? "Trust but verify." 13 (Laughter.) 14 DR. MARRETT: And it says a couple of 15 things there. In the case of Tuskegee, there was a 16 great deal of trust that those particular participants 17 had in the nurse, not in the researchers. In fact, 18 the nurse had to interpret often what was going on. 19 They trusted her a lot, but did that protect them? 20 Well, no. So there are other things that have to take 21 place. 22 So I think something like SACHRP has to be 263 1 concerned with both of the levels, as you've talked 2 about, making sure that there is the kind of trust and 3 trustworthiness that can exist through the level of 4 communication, through being clear about what is going 5 on, making sure that there is consent that is as 6 informed as possible but also making sure that there 7 are structures and systems and processes in place that 8 can go beyond. Is it only necessary for the 9 individual to trust the person with whom he or she 10 might be working? 11 I know that is not completely what you 12 were asking, but that is because I am leaving it to my 13 colleagues. 14 DR. HENDERSON: There is tremendous 15 distrust of the Indian Health Service delivery system 16 in many reservation communities in the country and, 17 arguably, with good reason. 18 Members of this audience may not know that 19 if you take the hospital's and clinics' budget for the 20 Indian Health Service and break it out across every 21 man, woman, and child beneficiary of that system, it 22 averages about $1,400 per capita expenditures on 264 1 health care for Indian man, woman, and child. 2 If you take every other federal health 3 care delivery system, Medicare, Medicaid, Bureau of 4 Prisons, Veterans Administration, anything else that 5 the federal government does, the average per capita 6 expenditures on health are around $3,600 a year. 7 So the Indian Health Service system -- and 8 this is popularly known among tribal people -- is 9 being under-funded to the tune of about a third of 10 what any other citizen in the country can enjoy if 11 they're a beneficiary of federal health care. 12 Of course, this is impacted by incredible 13 staff turnover at many of our Indian Health Service 14 facilities. Probably the second most common complaint 15 after the long waiting times is the fact that you can 16 never see the same provider twice, maybe not unless 17 you're seen in the same week. 18 So there's very significant distrust. We 19 don't see that rubbing off on us very much at all, 20 though. You know, there are situations like, for 21 instance, a perfect example is our providing 22 peripheral bone density screening for our cancer study 265 1 participants. 2 This is a service that in any other HMO or 3 whatever you would get, you could count on getting, 4 maybe not if you're 20, but certainly you could get 5 it. But you'll never get it in the Indian Health 6 Service. And we're able to provide that. So it's a 7 situation where, in fact, we're able to shore up and 8 fill in some of the holes that exist in the system. 9 The other thing that you should know is 10 that many Indian Health Service facilities are pretty 11 much general care only. Very few of the 41 hospitals 12 do surgery. Very few have intensive care units. 13 So a tremendous amount and types of care 14 that is needing has to be cared for through contracts, 15 contracts with other community hospitals or other 16 groups of cardiologists or gastroenterologists or 17 whatever the case may be. It's called contract health 18 care. There are four different priority levels for 19 contract health care in Indian communities: one 20 through four. 21 In the last decade or so in western South 22 Dakota -- and I know this is true of most places in 266 1 the Indian Health Service -- you will only get 2 referred for care and approved if you are a priority 3 one. What does that mean? That means that you are at 4 imminent risk of losing one of your limbs, one of your 5 senses, or your life. And if you're not, you'll not 6 receive approval for the facility to expend its 7 contract health for you. 8 So if you are 50 and older, are you going 9 to get a colonoscopy or screening sigmoidoscopy for 10 colon cancer? No, you're not. 11 MR. FORNEY: I am sorry. To understand, 12 your question I believe was related to public trust. 13 Is it? 14 MEMBER WEINER: It was really a question 15 of whether or not the doubts that you see in the 16 Tuskegee legacy -- or is there sufficient trust placed 17 at the beginning of this process? I think that -- 18 MR. FORNEY: What I wanted to say 19 regarding that, in that face-to-face, the initial 20 contact between physician, PI, and research subjects, 21 and one of the things which I was thinking is that 22 when information is presented to you and how far does 267 1 it go -- I look in my mind at informed consent that's 2 presented before me. 3 I think two things and somewhat to step 4 away from Tuskegee, to not refer to it. I think 5 somewhat of the anxiety is really just because of lack 6 of information, not so much that Tuskegee is on the 7 minds of everyone. But I believe what it is is just 8 that lack of information in regards to having that 9 trust there. 10 I think what is different today than was 11 then is we have something such as SACHRP, where there 12 is a body that's concerned and out there to ensure 13 that human research subjects are protected and that 14 they are not taken advantage of. 15 I think also, too, in that initial 16 face-to-face, when I am presented with a research 17 study, I know that there is the PI of the study. And 18 I know that there are any questions. I then have the 19 IRB over them to which I can go. 20 But after that, most study participants, 21 I would virtually say 99 to 100 percent of us, are 22 unaware of the other levels, such as the federal 268 1 level, SACHRP, who are governing these individuals to 2 ensure that what they are doing works in my best 3 interest as well. 4 I think it's just the issue is lack of 5 knowledge, unaware of the processes that are set in 6 place for human research subject protection that 7 perhaps some of the anxiety is there and the 8 reservations that are faced because the question is, 9 who is governing you, who is ensuring that you have my 10 best interest at heart. I don't know those answers 11 and those questions. 12 And that's one of the things that was 13 broached in the Baltimore meeting was in regards to, 14 if I recall, who is governing who, but I think more so 15 for study participants is when I participate in a 16 research study and this was my questions after the 17 malaria study was, well, what becomes of that 18 information? What has happened to that information? 19 It's not so much from a standpoint of: 20 one, was it successful at what you were trying to 21 achieve? And, secondly, did it benefit? Because why 22 would I participate in something that has no benefit 269 1 to anyone? 2 So I think patients need to know what they 3 participated in, what the outcomes have been because 4 I think that would engender trust to know that this 5 individual was working toward some endpoint. And this 6 is what the endpoint is in. And I know that my 7 participation in this and what you were doing with me 8 builds trust, you know. 9 CHAIRMAN PRENTICE: I think Felix was next 10 on the list. 11 MEMBER KHIN-MUANG-GYI: Thank you. I, 12 too, would like to add my appreciations for a very 13 informative and interesting discussion. 14 You know, at the circles of trust, public 15 understanding of research, things like coerciveness 16 and undue influence, they do sort of intersect in my 17 mind. 18 I don't know if you're familiar with Dr. 19 Kass' research. Nancy Kass following the death of 20 Ellen Roche wanted to see what the motivating factors 21 of folks participating in research were and followed 22 very much the type of thinking that you did: 270 1 demographics, reasons for participating. 2 I won't go into all of the details, but 3 what I found interesting was that money, while it was 4 a motivating factor initially for people to look at 5 phase I types of studies for non-therapeutic types of 6 studies, it was not the primary motivating factor. 7 There were other issues of socialization and social 8 environment. Getting the care and attention seemed to 9 override the dollar issues. 10 But, you know, RVs deal with money and 11 conflicts of interest and coercion in a way that 12 perhaps come up over and over again for us. And I 13 don't mean to distill this very complex issue that 14 you're talking about, but I wonder if you might speak 15 to the issue, all of you or any of you who are 16 interested, speak to the issue of compensating for 17 participating in research, although that really adds 18 or detracts at that level of trust, given the backdrop 19 of information that we have had. 20 DR. MARRETT: Actually, I have a little 21 quote from one of the pieces I was looking at. This 22 was a group of people who were sitting around talking 271 1 about research and reasons for participating. 2 And there was a volunteer in the group. 3 And the others asked her, "Why in the world would you 4 volunteer?" It was a group of African Americans. 5 She said, "Well, initially there was a 6 payment there." Actually, she went on to try to 7 justify, explain. She says, "It was a sleep study. 8 And they wanted to monitor me to see how I sleep." 9 And she said, "I thought it was a good study. It 10 wasn't going to do anything for me on a sleeping 11 disorder, but I thought this could be very helpful for 12 somebody else. And they can learn from it." 13 That level of sophistication there was I 14 think striking in a lot of ways because this wasn't 15 someone who was that well-educated. She had thought 16 she had come in for the financial reasons. 17 But yes, there's quite strong evidence 18 that that is not alone what brings people in that will 19 keep them because, as mentioned earlier, it's not just 20 a matter of recruitment. You've got to keep people in 21 studies for some time, too. 22 In those sorts of experiences, there is 272 1 enough there to say that we rarely can look for one 2 motivation that's going to cover all circumstances, 3 all people at all times. And certainly the idea of 4 money being the only force just does not hold up. 5 DR. HENDERSON: While we do compensate our 6 research participants in just about every one of our 7 studies, our study of 1,066 tribal college students 8 showed that the level of the compensation was well 9 down the list of odds ratios for factors associated 10 with whether they would choose to participate or not. 11 The single leading factor among both men 12 and women and across all ages was the salience of the 13 research topic, how important personally to the person 14 being asked to consider their participation, how 15 important was the subject of the research. 16 With diabetes, -- and many of you know the 17 incredible epidemic of diabetes has the number one 18 highest odds ratio of all possible factors. Cancer 19 was very high as well. 20 The level of compensation was not even in 21 the top five list of factors associated with 22 participation. 273 1 MR. FORNEY: And for myself, again, 2 initially, my desire to enter as a research 3 participant was not based upon money, though the first 4 study that I ever did paid quite handsomely. Let's 5 just say that. But it was my desire to know about 6 clinical research and specifically about the use of 7 humans in clinical research that prompted me to enter 8 into clinical research trials but also to, just as has 9 been said, this money weighs in. Money is a factor, 10 and I don't think that that can be excluded, 11 particularly when you are compensating the person for 12 their time; to some degree, the use of what they 13 considered to be their body, what they possess, and 14 things of that nature. So I believe that compensation 15 has always been and is an inducement for individuals, 16 possibly as a final inducement as to participate in 17 the study. 18 I may have these questions. I may have 19 this desire to help benefit individuals, but at the 20 same time, too, that you are willing to compensate me, 21 particularly, like, I would say, in this day and age 22 of our lives, our schedules, and things of this 274 1 nature, that you see me as someone that you're willing 2 to compensate me for the time, the effort that I am 3 taking out of my life to participate in an event such 4 as this. I think that will always be there. 5 That's something that one has to just pay 6 attention to. 7 CHAIRMAN PRENTICE: Nancy? 8 MEMBER JONES: I have two questions, and 9 I'll say them both because I know I will never get the 10 mike again. 11 CHAIRMAN PRENTICE: You are right. 12 MEMBER JONES: The first is just the 13 concept that, Dr. Henderson, you pointed out about 14 helping with the health care system, like buying those 15 machines and different things. And we looked at the 16 prisoners earlier in our deliberation. 17 I know there was some talk about whether 18 or not that in a sense, that becomes coercive because 19 you're improving the situation for medical delivery, 20 but then the trade-off is then you want people to be 21 willing to participate in research. 22 I know this is also in terms of long term 275 1 for like international, the same kind of thing that 2 when you build up an infrastructure for health care 3 but, really, the aim is also to get willing 4 participants. So just to talk a little bit about that 5 but, like I said, I wouldn't get the mike back. 6 The other question I have that we have 7 gone all the way around but just really want to hone 8 in, and that is asking how relevant culturally are our 9 current protections for your groups or are they 10 relevant? Are there ways that we can make them more 11 relevant for protecting human subjects, not for entry 12 in but, really, for that protection mechanism? 13 DR. HENDERSON: For your first question, 14 we're keen to pay attention to the possibility that 15 providing for routine care that's not otherwise 16 provided for could be coercive. In this particular 17 case; in fact, in all of our cases, we can be pretty 18 sure that it's not. And I won't say why I think that, 19 but clearly we're very interested and sensitive to 20 that fact. 21 On the flip side, there are many very nice 22 research questions to be asked around skeletal 276 1 metabolism, bone density, et cetera. So, in fact, it 2 was less to think this would bring people through the 3 door than the fact that that is a planned-for 4 ancillary study off of the main study. 5 Of course, NIH, the famous mandate that 6 NIH doesn't fund clinical care, right? We can't write 7 a grant to get funds to do screening colonoscopies on 8 people. 9 In fact, we're kind of beating our head 10 against the wall right now over a prostate and 11 colorectal cancer awareness study among Lakota men 12 that we would like to do and work through as 13 researchers those very issues and try to create a 14 fundable justification for us to receive funding to do 15 just that. 16 I mean, we're very clear. This point is 17 on a slide I didn't get to, but we are very clear with 18 our constituents what the quid pro quo is, very, very 19 clear. They make it crystal clear for us, and we make 20 it crystal clear for them in a way that academic 21 institutions generally are not, right? In fact, many 22 people are loathe to talk about the quid pro quo, but 277 1 we're not. So that's our philosophy. 2 MR. FORNEY: As a person who has 3 participated in research studies in the issue of 4 coercion, I will have to say in my experience, that 5 has never been something that I have had to contend 6 with. And it's never been something that with my 7 level of knowledge in working in research in and of 8 itself because with our studies, we are asking 9 patients to participate in certain research studies. 10 But personally that is not something of 11 which I have had to concern myself because the initial 12 information that has been presented to me is 13 information such that I make the decision. 14 And then once I am in contact with 15 research personnel, it's the opportunity that I have 16 to ask all the questions I deem necessary in order for 17 me to make a determination as to whether or not this 18 is something that I am interested in. 19 And today it's -- and, quite frankly, my 20 experience has been perhaps about 15 studies, which I 21 have participated in. And to date the issue I have 22 not felt that any particular researcher has tried to 278 1 coerce me in any way outside of the information that 2 they have presented to me in order for me to make a 3 decision. 4 DR. MARRETT: I think this is probably in 5 response to the second part, when you were asking 6 about how sensitive are the current procedures to the 7 kinds of community forces. I think it will vary, but 8 the one area that I think of that, again, will link 9 much of this around the matter of consent. 10 And I believe SACHRP is grappling with 11 what a number of groups have. And that is this matter 12 of group consent, where it's not a matter -- some 13 communities are so much more cohesive, if one wants to 14 put it that way. I think this is what you were 15 talking about for many Native American communities. 16 It's not a matter, then, of simply getting 17 from the individual but what does it mean to have 18 group consent. That's one of the ways in which 19 questions about culture then come into play. 20 Some of the others are not so much 21 cultural as socioeconomic. Our earlier discussion 22 about trusting the physician does not take into 279 1 account the fact that in a lot of low-income 2 communities, there is no physician, there is the high 3 turnover in the public hospital, and that you don't 4 have that kind of connection that can be there. Those 5 kinds of assumptions about what the whole structure is 6 just might not be very consistent with what the 7 practice is for a lot of people. 8 So I want to make a distinction, in part, 9 between what is cultural, what is a part of what a 10 group or community might have devised, and what is the 11 function of the economic status of the people who 12 might be involved. 13 CHAIRMAN PRENTICE: Tom? 14 MEMBER ADAMS: I would add my thanks to 15 the panel as well. It's been a real learning 16 experience to listen to you this afternoon. Over the 17 last two and a half years, when you stop and think 18 about it, what SACHRP really has been about is about 19 trust. It's about human protections, human subject 20 protections, but also about the underlying issues that 21 deal with trust. 22 Earlier the Advisory Committee looked at 280 1 issues that related to the accreditation of 2 institutions, whether they were sites, IRBs, 3 institutions involved in the clinical research 4 process. 5 We have also talked to a lesser extent 6 about certification of individuals as having 7 appropriate levels of knowledge. And I wondered that 8 for these two populations whether with the issue of 9 trust that type of accreditation and certification 10 would make a difference. 11 DR. HENDERSON: I am not so sure it would 12 make a difference for the better, but it can certainly 13 make a difference for the worse. We're doing what 14 most major academic institutions do, frankly, without 15 being a major academic institution. 16 We're a community-based organization, much 17 closer to the people than the typical institutions who 18 in the past have conducted a lot of research among our 19 people. And that carries with it a big plus. 20 It matters little that people may be 21 familiar with the organization per se but, rather, to 22 know that, number one, it's not the federal government 281 1 and; number two, it's not, you know, XYZ Major 2 Academic Institution who 20 years ago flew overhead in 3 a helicopter, dropped the ladder down, scurried 4 around, drew our blood, clipped our hair. Back up to 5 the helicopter they went, and away they went. By the 6 way, did we ever hear from them again? Those 7 situations are manifest around Indian country. 8 On the other hand, frankly, with the new 9 HIPAA regulations, they have done a lot, in fact, you 10 know. They now request us to say to whom we plan to 11 share our data, whether we have to send it someplace 12 else to get analyzed, whether we need to send 13 biological samples or a distant laboratory or 14 whatever. You have to spell out all of those 15 connections. And our IRB in our area makes us state 16 what our funding source is, differentiating the 17 government from private foundations or whatnot. 18 In fact, where I see people, you can see 19 folks. I have been there consenting lots of people, 20 reading their way through the consent form. And as 21 soon as they get to "Funded by the federal government" 22 and "Sharing data with," you know, you can see and all 282 1 the reluctance starts coming out. And that's where if 2 we have to clarify something, that we do. 3 So your point is well-taken. So more 4 pervasive efforts to accredit institutions to be made, 5 would that make a difference in Indian country? No, 6 I don't think so. 7 DR. MARRETT: I am not sure whether 8 accreditation would enhance the level of trust. If I 9 talk in this instance about low-income African 10 American communities, they're not likely to even know 11 that there is a whole accreditation system that has 12 been put into place. 13 But it's quite possible that trust needs 14 to be built at a lot of levels in so many different 15 communities. So one of the questions becomes with the 16 research community, with IRBs because that is a part 17 that has to be built, too, a sense that that is a 18 whole community that is going to build trust with one 19 another. That is really to protect the human 20 participants. 21 So I don't want to rule out the idea of 22 the whole accreditation process. I just am not sure 283 1 that is going to be put in place in order to enhance 2 the level of trust on the part of many of the 3 community members we are talking about, but it might 4 well have to be a part of an entire system for 5 creating something that brings everybody together. 6 And, in part, I think that's a function of what 7 happens as the accreditation process continues to 8 unfold. 9 I know that there are the developments 10 already, but what is built into the whole matter of 11 the accrediting organizations and to the extent that 12 those that accreditation will reflect these kinds of 13 concerns that emerge out of communities, then there 14 might be much more of a direct relationship than I am 15 able to see right now. 16 MR. FORNEY: Just to add something to what 17 Dr. Marrett is saying, that accreditation to a large 18 populous as a whole, particularly, as you say, a 19 socioeconomic population with not a lot of education, 20 to me they're somewhat not merely to say the ability 21 to comprehend but just general knowledge of what it 22 is. 284 1 But just, as with Dr. Henderson, from the 2 standpoint I would say with the African American 3 community to use as an example is that body of 4 individuals you may seek out in order to assist or 5 have assistance in order for this to be done. 6 Those who are deemed the leaders of this 7 institutions, potentially they themselves may be from 8 a higher educational and socioeconomic background who 9 are going to desire this information to know that if 10 you're going to have me influence anyone, I have to 11 have from you the knowledge that you are individuals 12 who are accredited that I can say that you are sound 13 in what you are doing because if something should go 14 awry or wrong, then individuals will come to me and 15 state that you influence this. 16 And then in the future, you may have an 17 even more potential problem on your hands to come back 18 to say, "We want to do something else." So 19 accreditation at a certain level is necessary and 20 would work well for you. 21 DR. HENDERSON: It occurs to me I should 22 make clearer my reason for not thinking that that 285 1 would make a difference. This dovetails with a 2 significant interest of mine, which is legitimacy 3 theory. And the brilliant sociologist Max Faber, who 4 some of you may know even much better than I, coined 5 the term "legitimacy theory" and said basically there 6 are three types of legitimacy in this country. 7 There's rational and legal accreditation 8 experience, of which the driver's licenses we have, 9 diplomas on the wall, et cetera, are all examples of 10 rational and legal legitimacy. There's charismatic 11 legitimacy in the world, unfortunately, and a few 12 cases, fortunately, have had leaders who by nothing 13 more than their mere charisma controlled millions and 14 carried out all sorts of actions in the world. 15 And then, finally, there is traditional 16 legitimacy. Traditional legitimacy, as was heard 17 here, is when you would walk into an African American 18 community or church and ask around about who is the 19 person we should talk to about this, who may well not 20 have any initials behind their name or any form of 21 rational or very little form of rational or legal 22 legitimacy but to the same extent, walk into a 286 1 traditional community and want to talk to a 2 traditional healer, where a community has a 3 traditional healer, and just ask around to a few 4 people. 5 And if you ask enough people, you'll see 6 that most of the fingers are pointing over there to 7 that man or that woman who is probably not graduated 8 from high school, who has been there in that community 9 for all of his or her life, who has been recognized 10 for decades to be doing good works with their hands or 11 their herbs that they know how to use and so who have 12 accrued significant levels of legitimacy through 13 purely traditional means that may or may not be very 14 charismatic. 15 And so in your case, you know, the 16 question really, then, is will it make any difference 17 to a community that values most traditional forms of 18 legitimacy to try to lay over the top another more, 19 better, more comprehensive, rational, and legal type 20 of legitimacy. That's basically why I don't think it 21 would. 22 And so that would be my point of 287 1 reflection back to SACHRP, to consider this particular 2 issue and how might the protections for human subjects 3 take into better account these pervasive in many 4 communities, yet pervasive forms of traditional 5 legitimacy. 6 CHAIRMAN PRENTICE: Okay. I'd like to 7 bring the session to a close and thank the panel 8 members for the very informative and interesting 9 presentations and dialogue. Again, thank you for 10 coming to SACHRP. 11 (Applause.) 12 CHAIRMAN PRENTICE: Moving right along, 13 we're going to go into the public comment period. And 14 we have two individuals who have signed up. There may 15 be others who would like to address the Committee. 16 The two individuals are from CIRCARE. I 17 assume that Liz is first on the list. She would like 18 to go first perhaps or, Mike, you are going to go 19 first. Okay. 20 And, for the record, of course, state your 21 name, affiliation. You know the routine. Thanks. 22 PUBLIC COMMENT 288 1 MR. SUSKO: Michael Susko. I'm President 2 of CIRCARE. 3 I wanted to start by simply thanking the 4 Committee for the opportunity to have folks who 5 represent more of the research subjects and advocacy 6 for their protection to come and present points of 7 view. 8 I think, rather than bring a new issue, 9 just simply to talk a little bit about the advantage 10 in doing so. One of them is that people were saying 11 things were interesting. It's not quite so boring 12 perhaps. 13 But on a more serious note, I think when 14 we get into the issues from the research subjects' 15 perspective, we tend to look at the whole picture, the 16 big picture, some of the meta issues, rather than 17 being always focused towards more of the micro roles. 18 And we can address things we may not have really 19 looked at so much; for instance, the notion of trust 20 and building trust with the research subject community 21 or the public citizens. That is a very important 22 issue. 289 1 I think that good science and good 2 protection of human rights go together because if you 3 don't have good human subject protections in place, 4 then you're going to injure people. You're going to 5 not have trust, and you're not going to have research 6 subjects to do the science. So it all sort of meshes 7 together ideally. 8 So we're looking at the big picture. 9 We're thinking a little bit outside the box. We've 10 got new perspectives we may not hear so much. Things 11 that we may be missing from our discussion are being 12 brought out. Also, there is a little bit of passion 13 being added by having people here that are directly 14 more impacted by research. 15 The process is kept alive. We know that 16 real people are being affected by all that's being 17 discussed here today. We applaud people. We sense 18 the altruism involved. So that's another good point. 19 Also, we sort of get a sense of cutting to 20 the chase, like what are the real significant issues? 21 Following the money trail, adverse event reporting. 22 We can keep our focus a little bit more when we 290 1 involve, you know, the real people that are the human 2 subjects here that are involved in human subjects 3 protections or the actual population that we're 4 concerned about. 5 So I'd like to ask the Committee with 6 those points in mind, can we institutionalize this 7 process a little bit? I know we have a special 8 session here. It's, you know, I think been to good 9 effect, but how can we make this ongoing a little bit 10 or is this sort of like going to be a one-shot deal? 11 Is there a way we could have like more ongoing 12 activity on the Committee or subcommittee? Maybe we 13 should do this every year. And so a year down the 14 line, we could ask, "Well, have things gotten any 15 better?" And we could present our views again. 16 So that is just a little bit of a request 17 or challenge even to the Committee to keep us 18 involved. 19 CHAIRMAN PRENTICE: Okay. Thank you. 20 Actually, I anticipated that question 21 would be asked sooner or later, "Is this a one-shot 22 deal?" No, it's not a one-shot deal. And we would 291 1 hope to involve the public in future SACHRP meetings, 2 certainly not every SACHRP meeting, because we have a 3 lot of work to try to get through in terms of the 4 subcommittee reports and recommendations. But rest 5 assured that this is not a one-time-only appearance or 6 invitation by people who represent subjects or 7 advocates of subjects. 8 We do have representatives on the 9 subcommittees. It's not a 50 percent representation, 10 but we do have representatives. Okay? 11 Liz? 12 MS. WOECKNER: I'm Elizabeth Woeckner. 13 I'm representing CIRCARE, Citizens for Responsible 14 Care and Research. 15 I saw you cringe at our blanket statements 16 that the human subject protection system is 17 ineffective. 18 The regulations talk about IRBs. They 19 don't tell me good IRBs. They don't tell me IRBs in 20 the State of Massachusetts at good hospitals. They 21 look at IRBs. And what we brought to the subcommittee 22 are the things we see, what crosses our desk. 292 1 The people who e-mail us, the people who 2 say, "Ah, there is something wrong with this. My 3 doctor gave me this big, long form. I don't 4 understand it," some of it is our personal follow-up. 5 Malaria therapy has got to be the greatest 6 irony that I have ever encountered. This year we were 7 privileged to read an awful lot of material, study 8 protocol, informed consent, from the malaria therapy 9 study conducted in China by Dr. Henry Heimlich and it 10 turns out helped along with NIH funding. 11 Here is a malaria vaccine study that a 12 subject was very, very pleased to participate in in 13 other circumstances. We were contacted by families of 14 infants who were harmed in clinical trials unbeknownst 15 to them, testing unapproved medical devices in cardiac 16 surgery. 17 One of us was asked to help out in a very 18 peculiar medical board case in which a principal 19 investigator in an ongoing NIH study was convicted of 20 selling laetrile to an undercover agent with the 21 Office of Criminal Investigation. We just need a few 22 little definitions there. 293 1 Adil and his colleagues were looking at 2 the Saturn trial last year. And one of the other 3 interesting things we have been following is a 4 criminal case in the United States District Court in 5 western Tennessee against an IRB member for his role 6 in the clinical trial. 7 I can't say we work in the ghetto. I can 8 say this is what we see. You're a wonderful teacher. 9 I would be delighted to sit in your anatomy class. I 10 can see how you can spread, personally you can extend, 11 human subject protection. There is a culture of 12 compliance. 13 Trust? I can evaluate you. I can look 14 you up on PubMed. I can talk to you. I see what 15 you're doing. A blanket statement is not entirely 16 accurate. But there's no way for anybody to tell. An 17 IRB is an institution, and they are of all qualities. 18 What we see is a variable quality. And 19 the recommendations of this subcommittee will affect 20 IRBs. And they are not a single beast. And I think 21 we're all rightly concerned with loosening things. I 22 trust many people to loosen. I'm scared because of 294 1 what we see. 2 Thank you. We appreciate the opportunity 3 to talk today. 4 FOLLOW-UP DISCUSSIONS/WRAP-UP/ADJOURN 5 CHAIRMAN PRENTICE: Okay. Thank you for 6 your comments. Let me respond. I'm not responding on 7 behalf of SACHRP or OHRP. I'm going to respond 8 personally, my own opinions. My colleagues may or may 9 not share my opinions. 10 I have been doing this a long time. And 11 I have come to some conclusions. One, I think the 12 vast majority of investigators are ethical and 13 well-intentioned. 14 There are going to be some outliers. That 15 is inevitable because of the human nature being what 16 it is. No matter what kind of an oversight system we 17 have, there are still going to be abuses. So that's 18 a given. All we can try to do is minimize those. 19 My second observation is that the vast 20 majority of IRBs really want to do the right thing. 21 Are they all equal? No, no, they're not. There are 22 somewhere around, you know, 4,000-5,000 IRBs. Adil 295 1 might say there are 8,000, but the figure is 2 somewhere, let's say, in between. 3 Is there variable protection across IRBs? 4 Yes, there's no question about that. Has that been 5 reduced over time, particularly since 1998? In my 6 opinion, the answer is yes. Will it continue to be 7 reduced? I hope so. Are our efforts directed towards 8 reducing inconsistency in terms of human subject 9 protection? The answer is yes. 10 Do we have a broken system now? I 11 hesitate to characterize it as broken. Do we have a 12 system that needs improvement? Then my answer is yes. 13 And if you ask me the same question five years from 14 now, I would give you the same answer. Yes, it still 15 needs improvement. 16 Was the system broken, as the OIG 17 suggested in 1998? You know, quite possibly. We had 18 IRBs that were just stressed to the max, overloaded 19 with work, under-resourced. And when the shutdowns 20 occurred, all of a sudden, the institutions found the 21 resources to quadruple the resources, quadruple the 22 staff. 296 1 Now, why did it take a shutdown for that 2 to happen? It's unfortunate that more institutions 3 aren't more proactive, but I'm beginning to see more 4 institutions becoming more proactive. 5 Now, are all 4,000 IRBs or all 4,000 6 institutions where IRBs are located all proactive? 7 The answer is no. Okay. Can we fix the system or 8 correct these deficiencies overnight? The answer is 9 no. All we can do is work towards that goal. And 10 that's what SACHRP together with OHRP and FE are 11 committed to doing. 12 The clinical research in this country is 13 a huge, huge enterprise. It's just you can't even get 14 your arms around it. We don't know how many clinical 15 trials are ongoing. We don't know how many research 16 subjects are enrolled in clinical trials. We have no 17 data. Okay? 18 We should know, yes. Yes. We have a much 19 better handle on how many animals are used in research 20 than humans. We should have this information. All 21 right? And we're talking about clinical trial 22 registries. We're talking about registries for 297 1 adverse events. These are things that are being 2 talked about, but they're not going to be accomplished 3 in the next six months or the next year. 4 So I'm comfortable that we're making 5 progress. Would I like to make progress more rapidly? 6 Yes, the answer is absolutely. Okay? But I'm a 7 realist. You know, when you want to make changes, you 8 have to deal with the federal government. And the 9 federal government sometimes moves, unfortunately, 10 slowly. Okay? 11 So, consequently, you know, I've tried to 12 develop patience. And for people who know me, they 13 know I'm not very patient. I want things to happen 14 instantaneously, but I've tried to be patient. Okay? 15 So I would encourage CIRCARE, who are 16 concerned about the same things that we are concerned 17 about, to have patience, provide us with feedback at 18 appropriate opportunities. We have invited you to do 19 that. That is why you are here today and that is why 20 we appreciate your comments. 21 Since I have invoked the inefficiency of 22 the federal government, Dr. Schwetz, perhaps you would 298 1 like to offer some further comments. 2 (Laughter.) 3 EXECUTIVE SECRETARY SCHWETZ: You're 4 patient? 5 CHAIRMAN PRENTICE: I'm not? 6 EXECUTIVE SECRETARY SCHWETZ: Well, I 7 don't disagree with what Dr. Prentice has said. And 8 I have said the same things in public and in other 9 places, that it bothers me when I hear people say that 10 the IRB system is so dysfunctional that it shouldn't 11 be used or that it's broken and needs to be fixed. 12 When I look at how it is that the system 13 of protecting human subjects has evolved in the U.S. 14 and look at what are the alternatives, it isn't 15 something that we can abandon and adopt something else 16 immediately for a seamless better protection of human 17 subjects because there isn't anything out there. 18 So I think SACHRP has shown a significant 19 commitment to reasonable improvement, not just pie in 20 the sky theoretical kinds of things that make for 21 interesting documents that stay on the shelves in our 22 offices and nobody ever reads. Instead, I think this 299 1 is a Committee that has rolled up its sleeves and 2 taken on the issues of the day and has been committed 3 to listening, not just talking. 4 So I think between what we are trying to 5 do in the federal agencies and what SACHRP has already 6 shown as a track record in these couple of years, I 7 just hope we can keep going and keep plowing more 8 ground with SACHRP in as much time as we have to do 9 that. 10 From the standpoint of whether or not this 11 is going to be a one-shot deal, it certainly wouldn't 12 be my intent that it would be a one-shot event either 13 because I think today was a very beneficial day for 14 me. It's important. Days like yesterday are 15 important, too, in terms of the technical things that 16 we go over about how to improve the gudiances, the 17 regulations, the interpretations, all of the things 18 that SACHRP has been talking about. That's kind of 19 the bread and butter of what SACHRP is about. 20 But the thing that, as one of you said, 21 lends a real sense of what we're here about is to hear 22 from subjects, from advocates, from the public, who 300 1 are really there experiencing what we hear from day to 2 day on the phone as complaints, what we hear in 3 meetings in the hallways, what we hear people talk 4 about on a regular basis. 5 That certainly does add legitimacy to what 6 this whole activity is about and creates further 7 incentive for doing those things right that we don't 8 quite have right yet. 9 I don't know if it should be on an annual 10 basis. I would remind you of something that Ernie 11 didn't say. We have public comment sessions in every 12 meeting. So the public is always welcome to come and 13 talk at our meetings. 14 And it doesn't have to be the topic that 15 just preceded the public comment period. You can come 16 and talk about whatever you want during that time. So 17 we would encourage that. 18 We're always open to communications by 19 letters, by e-mails, by telephone calls, whatever. So 20 it isn't that there is a window of time during SACHRP 21 meetings or some other kind of a meeting when we're 22 open to hearing from the public. 301 1 And one of the things that I have been 2 working on within OHRP as a priority is how do we 3 reach out to the public more than we have? We have 4 spent our time almost exclusively with the IRB 5 community, a little bit trying to reach investigators, 6 which is very difficult, even more difficult to reach 7 institutional officials. But that whole part of the 8 enterprise that doesn't include the public, that's 9 where a lot of us have spent our energies. 10 And in these past couple of years, I have 11 with the help of people within OHRP developed a 12 program of reaching out to the public to provide 13 information but, just as importantly, to create an 14 opportunity for listening so that they know who to 15 call, who to talk with, who to look for in meetings. 16 That is something that we're committed to as well. 17 So I would hope that as Ernie and I and 18 the others on SACHRP and the others within the federal 19 agencies talk about what are the priorities for 20 SACHRP, what are the priorities that are important to 21 the SACHRP members, to the federal agencies for SACHRP 22 to be working on or any one of the things that I would 302 1 want to keep on that list for sure is listening to the 2 public, listening to subjects, listening to patients, 3 listening to the advocates. I think that has to be a 4 continuing priority to help us understand where the 5 other priorities fit in. 6 So thanks for raising the points that you 7 have been. Thanks to those of you who participated as 8 speakers today to raise our awareness on women, on 9 minorities, on American Indians, on African Americans, 10 on people who have lost loved ones to research, to all 11 of the dimensions that we have heard today. 12 We won't necessarily revisit exactly the 13 same dimensions next time, but I think that's a lot of 14 the community that we need to continue to listen to. 15 So thank you for today. 16 CHAIRMAN PRENTICE: Okay. Any further 17 comments from SACHRP members? Tom? 18 MEMBER ADAMS: Just for a moment to think 19 about where we are, really, with the clinical research 20 process in this country and the role that SACHRP is 21 playing, the organization where I work has members in 22 some 65 different countries around the world. 303 1 And I can tell you that in most of those 2 countries, they aspire to reach the level of quality 3 in clinical research and human subjects protections 4 that we have in this country. It's not to say it's 5 perfect, but it is the best in the world as far as we 6 are able to see. 7 I think it speaks volumes about our 8 government, volumes about Secretary Thompson, now 9 Secretary Leavitt that they would create something 10 like SACHRP to be able to obtain the types of input 11 that we have had throughout our first two and a half 12 years and now beginning to get the input from the 13 public as well. 14 So I think this is actually a point in 15 time that we should, in fact, celebrate success. 16 CHAIRMAN PRENTICE: Thanks, Tom. Anybody 17 else? 18 (No response.) 19 CHAIRMAN PRENTICE: Okay. 20 MEMBER SELWITZ: Can I ask David LePay a 21 question? I just couldn't go all day and not ask FDA 22 something? 304 1 And, again, Ernie made some announcement 2 that I must confess I missed. So if this was part of 3 your announcement, I forgive you. You know, I was 4 very interested in the Subpart E, whatever level, even 5 if it's not a Subpart E. 6 And I just wondered how -- I mean, is FDA 7 engaged in this process at all? I liked the fact that 8 you had a Subpart D on children. I wondered how the 9 two fit together in this area as well, FDA and OHRP. 10 DR. LePAY: Yes. I would say that we were 11 certainly working together with OHRP in this area. I 12 don't know how Ernie described it when I -- 13 CHAIRMAN PRENTICE: I forgot to say 14 "joint," joint -- 15 DR. LePAY: It is a joint series of 16 discussions. 17 CHAIRMAN PRENTICE: Yes. 18 DR. LePAY: What we're looking toward is 19 really an answer to the question, what is the next 20 step to better protect individuals with diminished 21 mental capacities? 22 We're not convinced necessarily it is a 305 1 Subpart E at this moment, that rulemaking is the way 2 or the only way. That is the whole purpose of 3 committing to solicit public comments about how best 4 to take up this area. 5 And I expect, you know, our discussions 6 have been that we are going to develop this series of 7 questions that constitute an advanced notice of 8 proposed rulemaking as a joint effort and issue it 9 jointly and proceed as we can jointly to the extent 10 that our statutes allow us to have identity. 11 CHAIRMAN PRENTICE: I might make the 12 comment that there has always been a concern about 13 harmonization of OHRP and FDA guidance. And certainly 14 we heard that on our Subpart A subcommittee reports. 15 In my view, in working with OHRP and FDA 16 over the last two years, I have seen much greater 17 interaction than I ever saw prior to two years. 18 There's close communication between FDA, in 19 particular, David LePay and Bern Schwetz. There is 20 interaction between all of the members of the ad hoc 21 group that are on SACHRP. 22 So I think we are all trying to get on the 306 1 same page; whereas, I suspect that, you know, in 2 previous years, we perhaps were not on the same page. 3 So I am optimistic that we are going to have 4 harmonized guidance in the future. 5 I'm not going to say in the next six 6 months or the very near future, but I think it's 7 something that is going to happen. I think it is 8 something that needs to happen here. 9 I want to make one final comment on the 10 record for the benefit of OHRP and also the Subpart A 11 subcommittee. It pertains to equitable subject 12 selection and the inappropriate demographics of 13 accrual in clinical trials. 14 One of the things that the IRB has to do 15 when they review a protocol and approve it is they 16 have got to comply with 46.111 and the FDA 56.111, 17 which includes equitable subject selection. So they 18 take a look at the recruitment plan. And they need to 19 be assured that there are appropriate plans to recruit 20 a diverse subject population. 21 However, at continuing review time, few 22 IRBs in my experience are asking for the demographics 307 1 of that accrual. They're asking for the total number 2 of subjects accrued. Sometimes they're asking for 3 gender breakout, men and women, but they're not asking 4 for the demographics of subject accrual. 5 Dr. Carome, I notice in your progress 6 report guidance, you simply say, "number of subjects." 7 There is no reference to breaking that down to make 8 sure that you indeed can achieve equitable subject 9 selection. 10 So, Felix, I would encourage your 11 subcommittee to take a look at that issue as you look 12 at continuing review because it's not something we 13 talked about the other day. 14 MEMBER KHIN-MUANG-GYI: You are right. At 15 continuing review, I think that most of the folks that 16 sat around the subcommittee did not think about the 17 ongoing evaluation of that particular section of the 18 regulations. 19 Anyhow, I wonder if I might ask you more 20 of a practical question along those lines. What does 21 the IRB do with that data? What do IRBs that ask that 22 question ask of the investigators or the sponsors? I 308 1 mean, do they go back and say, "Stop your study until 2 you have a racially gender-balanced mix"? I mean, 3 what kind of authority does the IRB have or how do you 4 foresee this unfolding? 5 CHAIRMAN PRENTICE: Well, I can't tell you 6 what you do relative to sponsors. I can only speak on 7 behalf of what we do. I'm not suggesting it's 8 perfect, but we ask all that demographic information. 9 As a matter of fact, it's entered into a 10 database. And within about six months, we will be 11 able to tell you the number of subjects by ethnic 12 status, gender that have enrolled in every single 13 research protocol across departments, across 14 disciplines, according to PIs. You know, we could 15 really search the database for all of that 16 information. And that will be available in about six 17 months. 18 But right now when we review a protocol at 19 continuing review time, we do look at that 20 information. And when we see a disparity, when we see 21 there have been 100 subjects enrolled in the last year 22 and 99 of them are Caucasian and there is one African 309 1 American and we ask the question, "What is going on? 2 Why?" we do the same thing in terms of gender 3 disparity. 4 Investigators give us sometimes acceptable 5 answers, sometimes unacceptable answers. One of the 6 acceptable answers that we're concerned about because 7 it is acceptable, actually, is the fact that they say, 8 "I have approached every single patient who came into 9 the clinic, regardless of ethnic status. And I have 10 enrolled everybody who decided to participate," which 11 goes back to, for example, the Tuskegee legacy, where 12 if you approach some African Americans to participate 13 in a hypertensive study or a diabetes study or what 14 have you and they say, "No, I don't want to do that." 15 So what can we do about that? Well, we 16 have to overcome this mistrust on the part of certain 17 segments of the population. How do we do that? Well, 18 that was the thrust of my question to the panel. What 19 can we do? 20 I know in my medical center, we're looking 21 at trying to reach out to the community with various 22 kinds of initiatives of that sort because we suffer 310 1 the same problem. Our investigators have inequitable 2 subject selection, which they claim is not their 3 fault. 4 MEMBER KHIN-MUANG-GYI: I appreciate what 5 you are saying, and I agree in principle. Dr. 6 Henderson talked about the Havasupai. Even in our own 7 vernacular, we're not precise with what we mean and 8 what we say. 9 We talk about ethnicity. We talk about 10 race. One of the things that really offended that 11 particular tribe was that in the genetic analysis of 12 the migration patents, they found that there were 13 migration patents that link back over to -- correct me 14 if I am wrong, Dr. Henderson -- the Asian continent. 15 And that was a huge shock to that 16 particular tribe because of their tribal beliefs in 17 the genesis of the tribe being in the local area. And 18 this was a violation of their tribal understanding, 19 tradition, all those other things. 20 You know, we talked about the question of 21 race and gender. Let's just stay with gender for a 22 second. In 1993 and 1994, FDA and NIH, respectively, 311 1 came up with a guidance in the Federal Register about 2 equitable selection, female and minorities in 3 research. 4 The question was asked of the NIH folks, 5 is there some compilation of that information that 6 feeds back to the study sections? I served on a study 7 section for about two years. And I've never seen any 8 of that information come back to me in the studies 9 that I have either reviewed or rereviewed. 10 The FDA response that we have gotten back 11 when we raised the question with FDA, how do you 12 handle race and gender inclusion issues, is never 13 prospectively but more retrospectively. If the data 14 seemed suspect or if the data did not look right, then 15 we would look for further subgroup analysis. 16 And I don't know if that particular 17 position has changed. Dr. LePay, you can help us 18 address that. But it's not on a prospective basis. 19 So, you know, the wish back from the 20 sponsors and the investigators is the protocol may 21 call for some kind of parity, but there isn't any 22 leverage or real practical application of that. So I 312 1 wanted to make sure that we're not going down the path 2 of asking for additional restrictions or queries that 3 add to not so much the regulatory burden but more the 4 administrative burden that detracts from what an IRB 5 ought to be doing to help protect human subjects. 6 So I'm concerned about going down the path 7 of saying, you know, equitable selection and principle 8 is a good thing. Linking it to Tuskegee is I think a 9 good thing as well, but sometimes we get caught up in 10 the emotion of saying there's a specter of Tuskegee. 11 In reality, are we looking for, you know, 12 the answer of how many angels can dance on the head of 13 a pin? Those are the types of questions that I don't 14 know how to reconcile. 15 So when we talk about risk as an example, 16 things like the shuttle mission come to mine. I mean, 17 there is a certain amount of risk that is inherent to 18 research. And I think we have to accept a certain 19 amount of risk if we want to gather information and 20 conduct research. So I don't know how much collection 21 of data like that adds to the minimization of risk or 22 the protection of subjects. 313 1 MEMBER JONES: Can I say something? 2 CHAIRMAN PRENTICE: Not yet. The question 3 was addressed to me. 4 I understand your concern about adding 5 administrative loads, gathering data, what would be 6 done with the data, creating more hurdles for research 7 to take place. I understand that. 8 I am not so sure that it's an IRB 9 responsibility as much as I think it's an 10 institution's responsibility to provide service to the 11 community that it represents, the community that it 12 services. 13 I think it's important for a medical 14 center -- I don't care whether it is located in 15 Baltimore or they are located in Washington or San 16 Francisco or Omaha -- to be able to provide not only 17 treatment availability to the community they serve but 18 also the opportunity to participate in research which 19 may benefit that community. 20 And if we're not reaching that community, 21 whether it's Asian, African American, Native American, 22 if they're not enrolling in research which can benefit 314 1 not only them as individuals but their communities, 2 then I think we need to look at what is wrong. 3 We need to have some kind of 4 community-based outreach programs to try to correct 5 the situation. I have no idea how many academic 6 health science centers are engaged in those kinds of 7 outreach programs. I just don't know. Is it one 8 percent? Is it less than one percent? Is it 20 9 percent? I don't know. But I think that is something 10 we ought to be doing. 11 Now, who is going to get the data? Well, 12 it doesn't have to be the IRB that necessarily gets 13 the data, but I think the institution has to have the 14 data. 15 When I was asked a question by the vice 16 chancellor, "Can you tell me how many minorities are 17 enrolled in our research projects?" I said, "I can't 18 do that." I said, "If you give me an IRB number, I'll 19 tell you, but I can't tell you across the medical 20 center." 21 He said, "We really need that data." So 22 we're going to get that data because that is going to 315 1 form the basis for what we do in terms of outreach 2 programs. And I think that is important. 3 MEMBER KHIN-MUANG-GYI: It is if we agree 4 that medical centers are the only ones that are 5 conducting research. Unfortunately, you know, there 6 are many different models that add to the good that 7 you are trying to apply. 8 I think it is a very noble intent. And I 9 think that that is something that we ought to do. But 10 how do we apply that across the board? I mean, 11 unfortunately, we do have to have systems that allow 12 us to respond to the least common denominator. 13 And while the universities and the medical 14 centers are in a position where you want to be able to 15 look at that, how do we reconcile that with private 16 practice groups that are conducting research, clinical 17 research, to which this applies as well? 18 CHAIRMAN PRENTICE: Well, you're right. 19 And you're talking about the independent IRBs. 20 They're a different breed of cat, obviously. You 21 don't have the same problems that an academic health 22 science center IRB has. 316 1 I don't think that even if you get the 2 data, I'm not so sure what you could do with it. I 3 think the leverage would have to come from the 4 pharmaceutical companies, from the FDA with regard to 5 the data. 6 And another thing that was mentioned 7 earlier by Dr. Jones is that when you look at 8 publications, there is no demographic breakout of the 9 data. That's not normally done. Maybe journals ought 10 to reevaluate their publication policies and say, you 11 know, "We're not going to accept this unless you get 12 a breakdown." 13 You know, most investigators can get that 14 data. They can analyze it that way if they want to. 15 They just don't do it. 16 MEMBER KHIN-MUANG-GYI: One of the reasons 17 why you hear hesitation in my voice is that the 18 analysis of the data, you know, while inasmuch as we 19 would like for it to be a race-based discussion 20 sometimes cannot be on a race-based discussion because 21 I don't think we have the technology and the 22 ethnography and all of the other sophistication that 317 1 goes along with it to simply assign it to one versus 2 the other. 3 CHAIRMAN PRENTICE: 4 I think that the issues that we're talking 5 about I think go far beyond how an IRB does continuing 6 review and collection of those numbers and filling in 7 those boxes. Fundamentally that is what we are 8 talking about. 9 If we cannot have those numbers, all of a 10 sudden, then we're looking at an administrative 11 burden, for which many, many, many IRBs will be out of 12 compliance. 13 And so I think we need to recalibrate this 14 issue of equitable selection in a way that makes sense 15 that holds all of us accountable and perhaps have the 16 sophistication to be able to analyze the data because 17 I think you presented one aspect through an outreach 18 program, which makes sense from a university and 19 medical center side of things but may not make sense 20 from a true data analysis side. 21 CHAIRMAN PRENTICE: I don't disagree with 22 you. And I would suggest that you work this through 318 1 your subcommittee and explore all of those issues. 2 That is your job. It's not my job to do this stuff. 3 Okay? My job is just raise issues and questions. I 4 don't do any other work other than that, Felix. You 5 know that. 6 All right? Anything else? 7 (No response.) 8 CHAIRMAN PRENTICE: Okay. I'd like to 9 thank everybody for their patience. We have kind of 10 endured over the last three hours without any potty 11 breaks. So thank you very much. 12 Our next SACHRP meeting is on November 1st 13 and 2nd. So thanks very much, everybody. 14 (Whereupon, at 3:58 p.m., the foregoing 15 matter was adjourned.) 16 17 18 19 20 21 22