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 i