1 DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION + + + + + MEETING + + + + + WEDNESDAY NOVEMBER 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., Chair BERNARD A. SCHWETZ, D.V.M., Ph.D.Executive Secretary CATHERINE SLATINSHEK, M.A.Executive Director CELIA B. FISHER, Ph.D., Member NANCY L. JONES, Ph.D., Member FELIX A. KIN-MUANG - GYI, Pharm. D., Member SUSAN KORNETSKY, M.P.H., Member JAMES H. POWELL, M.D., Member ADA SUE SELWITZ, M.A., Member SUSAN L. WEINER, Ph.D., Member 2 Ex Officio Members PEG BARRATT, Ph.D., ,National Science Foundation SARAH CARR, National Institutes of Health 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 SALLY FLANZER, Ph.D., Agency for Healthcare Research and Quality DEBORAH HOLTZMAN, Ph.D.. U.S. Department of Health and Human Services DAVID LEPAY, M.D., Ph.D., Food and Drug Administration AMY PATTERSON, National Institutes of Health JOAN P. PORTER, DPA, M.P.H.U.S. Department of Veterans Affairs LAWRENCE UHTEG, M.D., Ph.D., U.S. Department of Commerce, National Institute of Standards and Technology ALSO PRESENT: KELLY BOOHER Office of Human Research Protections KRISTINA BOOROR Office of Human Research Protections MICHAEL CAROME Office of Human Research Protections JULIA GOREY Office of Human Research Protections IVOR PRITCHARD Office of Human Research Protections KEVEN PROHASKA Office of Human Research Protections IRENE STITH-COLEMAN Office of Human Research Protections 3 I-N-D-E-X AGENDA ITEM PAGE IOM Update: Report on Research Involving Prisoners . . . . . . . . . . . . .7 Update of FDA/OHRP Joint 407 Review Process. . . . . . . . . . . . . . . 50 Identification of SACHRP Priorities, Ex Officion Presentation. . . . . . . . . . 87 - International Research. . . . . . . . . . . . . 87 - Multi-Center Studies. . . . . . . . . . . . . . 99 - Evidence-based Practice . . . . . . . . . . . .110 - Exemptions. . . . . . . . . . . . . . . . . . .124 Discussion. . . . . . . . . . . . . . . . . . . .128 Public Comment. . . . . . . . . . . . . . . . . .169 Identification of Future SACHRP Priorities, Discussion. . . . . . . . . . . . . . . . .190 Public Comment. . . . . . . . . . . . . . . . . .269 4 1 P R O C E E D I N G S 2 (8:36 a.m.) 3 DR. PRENTICE: Good morning everybody. 4 I'd like to welcome you to the second day of our 5 SACHRP meeting. As usual, I will overview the agenda 6 for today. The first presentation will be an update 7 from the IOM's work on research involving prisoners 8 given by Larry Palmer. And I want to apologize to 9 Larry for awarding him an M.D. He's a lawyer, and I'm 10 sure this is a downgrade, okay, to get an M.D. for 11 him. And I will introduce him in a moment. 12 From 9:30 to 10:15, we're going to have an 13 update on our 407 review process which involves both 14 OHRP and FDA at times. And that will be given by Sara 15 Goldkind and Kevin Prohaska. 16 Then we have a break between 10:15 and 17 10:30. Then we get into an interesting section of our 18 meeting. That is the Identification of Future SACHRP 19 priorities. And we have identified four areas: 20 international research, multi-center studies, 21 evidence-based practice and exemptions, but there are 22 other things that will be on the table. And we're 5 1 going to have SACHRP ex officios presenting to us and 2 interacting with us. 3 Lunch is 12:30 to 1:30. And then we're 4 going to go into a session called Identification of 5 Future SACHRP priorities. We will talk among 6 ourselves. We will also interact with the ex officios 7 and OHRP to try to identify what future directions we 8 wish to go in. 9 We'll continue our discussion between 3:15 10 and 4:15. There will be a public comment section 11 between 4:15 and 4:45. And then we'll hopefully wrap 12 up at 4:45 or perhaps even earlier. 13 So I want to remind everybody of our 2006 14 meeting dates. I assume you have them on your 15 calendar. March 13th and 14th; July 31st, August 1st; 16 and November 2nd and November 3rd, 2006. All right. 17 Now, if Mr. Palmer would come up here, I 18 will go back to the table and introduce you. 19 As you know, the culmination of our 20 Subpart C committee's deliberations resulted in a 21 contract being given to the IOM to look at the ethical 22 basis upon which any proposed changes in Subpart C 6 1 should be based. And the IOM has been very, very 2 active in terms of pursuing that particular charge. 3 And Larry Palmer is on the IOM Committee. And I'd 4 like to tell you a little bit about him. 5 He is the endowed chair in urban health 6 policy at the University of Louisville. He has 7 appointments in the Department of Family and Community 8 Medicine, the Institute for Bioethics Health Policy 9 and Law, and the School of Public Health and 10 Information Sciences. But prior to going to 11 Louisville, he was a professor at Cornell University 12 Law School in Ithaca. 13 Professor Palmer is the author of Law, 14 Medicine: A Social Justice; Endings and Beginnings; 15 Law, Medicine, Society and Assisted Life and Death. 16 He's got an awful lot of articles dealing with law, 17 medicine and health policy. This is particularly 18 interesting -- I don't know if you know this or not, 19 but Professor Palmer is also the executive producer 20 and author of the study guide of the prize-winning 21 educational video, Susceptibility to Kindness: Miss 22 Evers' Boys and the Tuskegee Syphilis Study. 7 1 He is a member of Board of Directors of 2 Hastings Center, in Garrison, New York; and he's a 3 member of a whole lot of other organizations which I 4 will not name. So we're grateful that you have agreed 5 to come and talk to us today, and we're looking 6 forward to your presentation. 7 IOM UPDATE: REPORT ON RESEARCH INVOLVING PRISONERS 8 MR. PALMER: Well, thank you very much. 9 Also, thank you very much -- I'll say that before we 10 get into the hard part of our work. Thank you very 11 much for the opportunity to look at this important 12 problem. 13 For those of you who may not remember that 14 you're the sponsor -- the National Academies cannot do 15 its work without sponsors like yourself and -- we have 16 this committee on the ethical considerations for 17 revisions to the DHS regulations for protections of 18 prisoners involving research. I assure you our report 19 will not have that title. We'll get somehow beyond 20 that at some point. 21 But I'm just going to review with you the 22 statement of charges. You can follow along here. And 8 1 how this is framed for us. One of the overall 2 purposes of our committee is to examine whether the 3 conclusions reached by the 1976 national commissions 4 remain appropriate today. Some of us on the 5 committee, as I explained, have a peculiar 6 relationship to those recommendations. 7 When I was a much younger child, a younger 8 professor when I first went to Cornell, I actually 9 wrote a paper for that commission back in 1975. And 10 as I'll explain, one of the members of our committee 11 were there almost like staff to the '76 commission. 12 So we've got to sort of update our own knowledge. And 13 for me, it meant suspending the framework that I 14 thought I had when I was a slightly younger person in 15 order to look anew at this problem. 16 And what we're specifically trying to do 17 is to see what in the modern context are the -- what 18 today would make research with prisoners significantly 19 different from research with people who are not 20 prisoners. And we're hard at work trying to develop 21 an ethical framework for working with prisoners or 22 doing research with prisoners that's consistent with 9 1 a possible new ethical framework. We're going to look 2 at the safeguards, identify issues and needs for 3 future studies and consideration. 4 Now, the whole purpose of our studies and 5 our report is to give back to you a framework that you 6 might use or someone might use to revise the 7 regulations, if that's what we ultimately come up 8 with. I'll tell you a little bit about our committees 9 and how they're selected, or supposedly selected. One 10 of the things that the National Academy prides itself 11 on when you get into something this difficult for the 12 society, and somewhat controversial, is trying to get 13 a group of people who represent perspectives and who 14 do not have bias. That is, they have enough expertise 15 around the table so that you can do the job that we've 16 been assigned, but to make sure you have good 17 representation. 18 So the committee chair is Larry Gostin who 19 is associate dean for research at Georgetown and a 20 well-known scholar in public health. The other 21 members of the committee are a series of folks who are 22 either kind of card-carrying bioethicists or people 10 1 who have done research in prisons. 2 We are also very pleased to have Nancy 3 Dubler as not just as an advisor; I think we call her 4 an expert advisor to help make us aware of the issues 5 that led to the subcommittee to recommend that we 6 conduct this study. When we got formed, we go through 7 a very formal process of filling out -- we have to 8 actually -- it's almost like a disclosure 9 questionnaire from a special interest group. 10 You fill out the questionnaire. You tell 11 what you've done in the past, what positions you may 12 have taken publicly or your scholarship that might 13 affect it. That's sort of gone through, and then we 14 look around the table and say, "Do we have everyone we 15 really need?" 16 And two issues came up. One, do we have 17 adequate representation of people who have recently, 18 frankly, been prisoners or experienced prisons? And 19 do we have enough representation of folks who've 20 actually administered -- run prisons today under the 21 present conditions? Many of these of folks, some of 22 these folks have done research in prisons or worked 11 1 with community groups. We felt there was a 2 deficiency. 3 What we did on one hand is we decided to 4 invite someone who had been a former correctional 5 official to join us. That's Steve Cambra who had 6 worked extensively in the California system, which is 7 one of the country's largest systems, but who had 8 recently had taken early retirement. So he was not 9 presently under the political pressures of having to 10 run a prison, but it turns out when I explain to you - 11 - turned out to be a very useful addition and got us 12 access to some things in California which I will 13 describe to you briefly. 14 So we added him to the committee, and I 15 think to say about Steve: anyone concerned about the 16 conditions of prisoners, if you've met this person who 17 has run San Quentin -- if you know anything about 18 California, Pelican Bay is the supermax prison. If 19 you met Steve, it would give you hope because of his 20 insight into how to deal with the very severe problems 21 that we had. And we're very pleased to do that. 22 The other thing we decided to do was to 12 1 form -- this is unusual in this group -- but to form 2 a particular prisoner liaison group. And we felt we 3 needed this group to interact with much more actively. 4 Some of these names you may recognize. I think Allen 5 Hornblum is the author of Acres of Skin; Everett 6 Anthony is a prisoner who served in the Holmesburg 7 prisons back in the `60s when I was a law clerk for 8 Judge Higginbottom. Some of these folks, all of these 9 folks I believe have presented to us. Some of them 10 have recently been in prisons, are very articulate. 11 And as I'll tell you later, a subgroup of our 12 committee is meeting with this group next week on 13 November 8th to really kind of review with them issues 14 that we are considering. 15 Most of the deliberations delivers the 16 process in which we operate is that Congress allows us 17 to operate without public meetings. We have a public 18 session, but we can deliberate in private. So this 19 session is a little different because it's not 20 private, but it's not public with the prisoners, but 21 we really want to make sure that we keep in touch with 22 this group, and make sure that we get some impact from 13 1 that group. 2 We've found a lot of other folks have come 3 in and talked to us, and I'll talk about them shortly. 4 But those are two ways in which we ensure that our 5 deliberative process as best we can do gets the full 6 view and wisdom that we try to have in all of the 7 reports from the academies. 8 We've been meeting since we got formed 9 last February. We've met in Washington several times. 10 We met out in California on June 18th. I'm going to 11 describe that to you. We met recently. As I've 12 already told you, we're going to meet, I think five or 13 six members of our group are coming back to Washington 14 to meet. And we're having our final meeting here in 15 Washington in December. 16 Our hope is to have our report out -- our 17 hope and our plan is to have our report out or ready 18 for release near the time your first meeting in March 19 of 2006. So we're on schedule, we think, if we make 20 the progress this next couple of months that we hope 21 to. 22 Let me tell you about how some of those 14 1 meetings -- just give you a flavor about how some of 2 those meetings would work and talk a little bit about 3 the California visit in the context of data 4 collection. 5 We try to get as much information as we 6 can. That is, we have people around the table who 7 would know who's writing in the field and so forth. 8 So we have commission papers from experts or people 9 who would sit down and really write something for us 10 that we can use as the basis of our report or put in 11 the appendix, depending on how the report is 12 fashioned. 13 We have research assistants from the 14 National Academy staff, our consultants to help us do 15 literature reviews. And we've doing some actual 16 interviews with the Department of Corrections and 17 surveys to see what's really going on in prison, 18 because the scope of Subsection C is limited. And 19 that is turning out to be a very, very interesting 20 process and it's been very, very helpful to have folks 21 who have worked around the country and we said, "We're 22 going to send an email to the Department of 15 1 Corrections and in State X." And they'll say, "Send 2 it to Jane Doe because she is really the person who 3 does the survey and evaluation work there." 4 The site visits, we decided to meet on the 5 West Coast which is part of our obligation to make 6 sure we go around the country and people -- you can go 7 to the website and see all the stuff we're doing. But 8 because of the membership on our committee, we had 9 access -- we took an extra day. 10 I was going to go bike riding, but 11 instead, you said, "You went to San Francisco in 12 July?" "Oh, yes." "What did you do?" Well, we went 13 to San Quentin in the morning and then we went to 14 Vacaville in the afternoon. San Quentin, for those of 15 you who like living in gated communities -- I'd never 16 seen San Quentin. But it's got a beautiful view of 17 San Francisco. It has an absolutely gorgeous view of 18 San Francisco. 19 And I live in -- I just moved to 20 Louisville. I live downtown in what's called Old 21 Louisville, sort of a historic part of town like Old 22 Town Alexandria. And folks live out in gated 16 1 communities in the suburbs. I said, "I've got a great 2 gated community for you." Historic house. San 3 Quentin, as you may know, one of the -- seriously, any 4 of you familiar with -- I think Professor David 5 Rothman's (ph) book, Discovery of the Asylum, talks 6 about the early prisons built in this country -- 7 Albany Prison in New York and so forth. San Quentin 8 was built in 1870, so it's an old -- it's like in the 9 movies, "Cell Block" and so forth. 10 It's reputation -- the nice thing of 11 having Steve with us when we went through that prison 12 is that it was like being with the mayor of San 13 Quentin. The guards, the prisoners -- some of the 14 prisoners -- all knew who he was and so forth. But 15 that was a facility that's interesting because 16 despite its image, it has three functions: it is the 17 reception center for all people going into the 18 California prison system from northern California, not 19 the Southern part. Enormous place. 20 It is also a medium security prison. It's 21 no longer a maximum security prison. It's an old- 22 fashioned prison, cell blocks five stories high, two 17 1 men to a bed. The aisle between the wall and the beds 2 is not big enough for me to walk down straight. This 3 is a medium security prison. It also is where the 4 600-plus men who are on death row are held in 5 California. So you have three different functions 6 there. 7 The interesting thing about that prison -- 8 there have been about eight or ten prison guards 9 killed at San Quentin. The most interesting thing 10 about that visit was how -- what a prison has to do 11 today to control the level of violence. Most of our 12 images of the prison is interested in security -- no, 13 the prison is organized around protecting the 14 prisoners from each other and themselves. The most 15 striking thing for instance that I noticed -- when I 16 was -- when I first started my teaching career in 17 1970, I taught criminal law as well as human 18 experimentation, so I've been at this business a long 19 time. So I've been in prisons before. 20 The most striking thing about San Quentin 21 is, there are no weapons. Period. That's one of the 22 things -- no weapons inside that prison. And you say, 18 1 "Why not?" Because if there are weapons on the 2 guards; those weapons could be taken and most of the 3 people killed. They've actually done a lot of 4 thinking and evaluation of what causes the violence. 5 The other thing, because it's California, 6 of course, the prison is open in large openings and so 7 forth. You will immediately notice if you look at the 8 yard, which you can see, is that it is ethnically and 9 racially segregated. African Americans or blacks are 10 in one part of the yard; Hispanics in another; the 11 Aryan white nation people are in another part of the 12 yard; Asians in another, and so forth. And that was 13 a very strange notion. 14 The thing that sounds very strange and 15 people asked what it was like, how do you control -- 16 what's the goal? How do you control that? Okay. A 17 person on death row needs to go to the clinic. That 18 person has to be moved from one section of the prison 19 to another section of the prison. They have a system. 20 I think people like Steve had thought of this. 21 They sound an alarm and every prisoner has 22 to sit down. You say, "Why do they do that?" The 19 1 guards on the towers do have rubber bullets that will 2 really hurt you if they shoot them, and they can see 3 everything in the yards and so forth. And it seems 4 very strange, but then you watch this happen and then 5 you will see two uniformed officers come through all 6 dressed in vests, holding nightsticks and so forth, 7 escorting a person who is chained. 8 A prisoner who is on death row has to be 9 totally under custody whenever he's moved. And what 10 they're really afraid of is some other person coming 11 up and stabbing that person because he's unarmed. If 12 you're here, chained here and chained around your 13 waist, you're totally defenseless. Thirty percent of 14 the prison guards at San Quentin in California are 15 women. The main way in which they control people are 16 with their nightsticks, and we saw them training and 17 so forth with it. Just a very interesting experience. 18 Your image of what -- of course, I'd been 19 in a maximum security prison in Jersey when I was 20 teaching, is a very -- this is not maximum security. 21 At that prison, we got a chance to talk to folks who 22 act as I guess as a research project as lay kind of 20 1 health educators who try to educate the folks coming 2 in, in reception as to the health issues that they're 3 facing, AIDS, HIV, immunization and so forth. 4 So we did get some chance to interact with 5 folks. I think folks who went on that found it 6 extremely interesting. It just took -- at least for 7 me, someone who's been in the prison -- took away the 8 image of what do you have to do. You hear about all 9 this stuff, but you're actually running this game. 10 The Hispanics actually are divided into 11 two groups: northern and southern California; those 12 who are recent immigrants, those who are -- Instead 13 of trying to control the gangs, they're trying to put 14 safety -- safety is the main sort of -- at least my 15 observation -- the main organizational principle 16 there. You can think of someone thinking about 17 corrosion, you can also think of someone thinking 18 about safety. Those are two different kinds of 19 problems. 20 At the end of the visit, we got a little 21 tour of the death chamber and a little lecture by the 22 Assistant Warden on how they do that and so forth. I 21 1 think most of us came away with a great appreciation 2 for the dedication that most of the people who work in 3 the prison system. 4 The one small thing you notice in 5 California -- it happened at Vacaville -- is that if 6 a correctional officer -- they don't like being called 7 guards -- does not know the name of a prisoner, he's 8 always addressed as Sir. California, of course, has 9 been subject -- it sets a different tone. I say this 10 introduction to explain Vacaville. 11 Vacaville is out in the -- about 30 miles 12 east out in the Valley, about 35 degrees higher. It's 13 about 100 degrees, 95 degrees when you get out there. 14 It was 60-something when we left San Francisco. 15 We spent the afternoon at Vacaville which 16 is the medical facility for all of California. We had 17 had a presentation, I think, from Dr. Beck. He's on 18 our liaison committee, who is the medical director 19 there in our public meeting who is one of the 20 researchers -- and we listened to researchers, too. 21 He's a clinical director there, does correctional 22 health. 22 1 That facility is interesting. About 3,000 2 people there. That facility is interesting in that it 3 get to show you the long-term effect of long prison 4 sentences. If there are 900 -- 600 people on death 5 row -- some of them have been 25 to 30 years -- many 6 people are going to die in prison. And you might 7 think that the primary cause of death in prison would 8 be something like HIV. If you did, I think your data 9 is about ten years out of date. Most people are dying 10 of kidney failure, cancer, et cetera, diabetes and so 11 forth. 12 The most interesting part of the Vacaville 13 -- there was two. Vacaville has the only hospice 14 inside of a prison. And you say -- and some say I 15 tell a -- a liberal friend of mine that, "Why are 16 these people who murdered and so forth, why do they 17 have to have a hospice?" 18 Well, I think the reason why they have it 19 is that the more professional of the guards -- there 20 are bad people everywhere -- realize that any 21 opportunity to treat the prisoners with humanity 22 actually makes the prison work better. So they have 23 1 a system by which there are volunteers. Anyone who is 2 actually on a death watch has a 24-hour vigil; someone 3 sits with that person 24 hours a day. The goal being 4 that no one dies alone. 5 The hospice, if any of you have been in a 6 residential hospice -- when I lived in Ithaca, we 7 actually lived near it; it looked just like a resident 8 hospice. It had flowers in it, it had little garden 9 outside. They had taken care to put slats across the 10 windows so that the bars would not be the first thing 11 you see and so forth. Part of this open full mantle 12 wall -- room, televisions and so forth, 24 hour 13 visits. The other side was locked because the prison 14 has to follow the custody. 15 I say someone on death row -- someone on 16 death row at San Quentin is in their cell by 17 themselves except one hour a day. If you were moved 18 to Vacaville, you'd also have to be by yourself. You 19 can not be in the prison population. And people found 20 that extremely interesting. And who did it? It's the 21 staff. All that stuff was done by the staff -- the 22 nurses who worked there, volunteers in the community 24 1 and so forth. 2 The second thing is that we had another 3 chance to talk to folks who acted as lay health 4 educators in the community. And we got some useful 5 ideas from them, which is actually facilitated by one 6 of the wardens and so forth there. After that, we 7 decided we had enough expertise around by other 8 prisoners so that -- and some of them, the committee 9 says, "That's not the way they do it in Florida." We 10 felt we could go through this again. It's actually 11 quite -- not just time consuming; it's quite 12 emotionally wrenching to do this. 13 But we found it extremely enlightening and 14 we think our report will have a kind of -- not just -- 15 we hope the report will be analytically clear and 16 clearly written and so forth, but we also hope it has 17 a kind of voice and edge that says, "Prisons are 18 different than what they were before." And all the 19 data that we're gathering, all the demographic data, 20 I think will have a much more powerful impact. 21 Not everyone on the committee could stay 22 for that extra day, but those of us who did, I think 25 1 found it quite inspiring in a funny kind of way. It's 2 tough. It's a tough situation. But they're bad 3 institutions, but they're good people trying to do the 4 best they can under the circumstances. And there are 5 obviously some institutions you probably could never 6 do research in. 7 Pelican Bay -- what happens in prisons, 8 those of you who know the prisons, you violate the 9 rules, you're going to segregation. There's not just 10 -- there's segregation for X number of days. You 11 violate the rules more, you're moved from minimum 12 security up to maximum security. You fail in maximum 13 security, you're going to Pelican Bay which is 14 supermax, where things are much, much tougher. 15 So although San Quentin looks tough, 16 there's -- it is much, much tougher as you go down. 17 And I think the prison, particularly at Vacaville, 18 could explain to us that those who are not suffering 19 from mental problems and so forth understand that 20 system. 21 So where at Vacaville and one of the -- 22 their alarm system is different. Theirs, when the 26 1 alarm goes off, you have to step behind a line. Okay. 2 And there was an elderly prisoner sort of toddling 3 along who may not have heard the alarm or could not 4 respond fast enough, and I remember Dr. Beck saying to 5 him, "Sir, would you please move back behind the 6 line?" Because if he doesn't get behind the line by 7 the time whoever they're moving, that's technically a 8 violation. And this kind of grew with that prison 9 population. 10 It was a very different situation from San 11 Quentin. San Quentin, you have all these -- people 12 have different colored uniforms. The people in the 13 orange suit are the new people, usually unfortunately 14 returning to prison, the reception center. And 15 they're the ones screaming and -- well, not screaming, 16 but trying to make their way. 17 And then you go to Vacaville, where people 18 are in wheelchairs or who have had amputations, just 19 a different pace. And it was maybe 95 degrees in 20 those cells. And there are regulations on what they 21 have to do when it gets that hot. But the new clinic 22 that they've got, thanks perhaps to the litigation 27 1 that's put the whole California system -- medical 2 system for prisons under receivership is air 3 conditioned; it's new; it looked a little bit like the 4 examining room at my doctor at University Hospital in 5 Louisville. So we have a good feeling for what's 6 going on out there. 7 Sorry to go so long on that, but I think - 8 - I guess it's an example of the depths to which we 9 are trying to go to make sure we fulfill our 10 obligation to you, our sponsors. It wasn't exactly 11 your usual California/San Francisco experience, to 12 stay an extra day to go to prisons, but I think it's 13 going to help our work, at least my work a great deal. 14 So basically, the process that we go 15 through with something like this, you give us a 16 charge; we form the committee; we do research; we get 17 the consultants; we meet; we deliberate; we prepare 18 our report. Our report will be prepared. What's 19 going to take us so long to get it to you is that it's 20 got to go through a very extensive internal peer 21 review before it comes out to you. 22 There will be people who we don't know who 28 1 will be appointed to review our report, and that also 2 will be reviewed internally by Dr. Feinberg and his 3 staff. And then the report goes into production and 4 you get it. 5 This last slide explains our process 6 graphically. When I was at Cornell, at one point a 7 vice provost, it's an administrative position, and 8 back in the `60s there was a gentleman who was the 9 vice president for planning who was the dean of 10 architecture and had kind of a quirky mind. So he 11 made up a fake planning document. In the old days, 12 this would be long. And the document had on the front 13 cover a picture of the board of trustees. These are 14 your typical robber barons, you know, cigars and so 15 forth. Then you open it up and there was the 16 organizational chart at Cornell. 17 And it looked a little bit like this, 18 except at universities, the top person who has the top 19 box, was the traffic bureau. Our process is 20 complicated -- the editing, the transcription and so 21 forth -- but the ultimate goal is to produce a high 22 quality consensus report among people from different 29 1 backgrounds with different expertise that is evidence- 2 based with some practical wisdom from people who -- 3 it's primarily an evidence-based document that will 4 help you achieve your goals of looking at possible 5 revisions of Subsection C. 6 So that concludes my report. I'd be 7 pleased, Mr. Chairman, to answer questions. 8 DR. PRENTICE: Thank you very much for a - 9 - really a fascinating presentation. Asserting the 10 Chair's prerogative, as everybody knows I always do, 11 I get an opportunity to ask a few of the first 12 questions. 13 Obviously, you've been thinking a great 14 deal about the issue of research involving prisoners 15 and the differences between the 1970s when the 16 National Commission issued their report and current 17 conditions in the penal system. You talked about 18 different types of prisons. You talked about San 19 Quentin as being a medium security, Pelican Bay a 20 supermax, Vacaville, a medical hospital facility for 21 northern California. 22 Do you think -- I guess my first question 30 1 would be: do you think that we're not doing enough, 2 in particular I guess clinical research, in prisons in 3 general, perhaps because of the restrictions that are 4 in Subpart C? That would be my first question. 5 Followed by: do you think that the prison authorities 6 are supportive of having more research or really any 7 research in the prisons? And then the third question 8 would be: considering the differences in security 9 measures at various prisons, are there circumstances 10 where, you know, you just can't do research within a 11 prison? 12 For example, utilizing Pelican Bay. Maybe 13 it's just not possible to do research there, but 14 perhaps it is. I just don't know. So do you think 15 there's going to be -- if we end up doing more 16 research in prisons, is there going to be disparity 17 based upon the type of prison that exists? 18 MR. PALMER: Let me try to answer all 19 three questions together, if I can. But I think our 20 data gathering process is really trying to determine 21 your first question. That is, how much is going on 22 right now. We don't know the answer to that yet, and 31 1 we will present some data about our impressions or the 2 best that we can gather. 3 The second point of whether or not people 4 are supportive, I think we're taking -- we are looking 5 at the question of research as it's defined presently 6 in the regulation, but we're also looking at it more 7 broadly than that, I believe. Because one thing I 8 think we have noticed since 1976 is that -- 9 particularly on the behavioral research side, there's 10 a lot more interest in gathering data which may not 11 meet the definition of research. 12 So I think we're trying to kind of go on 13 that frontier. What I mean, for instance, is research 14 in the regulations has one definition, but it may make 15 a difference what you're doing. You may, for 16 instance, even in a Pelican Bay, there may be some 17 things you want to evaluate. Let's say at Pelican 18 Bay, I think they actually do try to control the gangs 19 because it's -- okay. 20 You might want to evaluate how effective 21 some of those techniques are. Now, you may not -- 22 that may not meet the definition of research, but it 32 1 may be data that is very useful that we might want 2 shared with other folks; that X technique did not work 3 in California. And we're trying to ascertain those 4 kinds of things or quality improvement. The other big 5 area that people worry about, particularly people with 6 public health interests, is what is really the status 7 of the populations. You know, there have been reports 8 in the past of TB outbreaks in prisons. You may be 9 monitoring and gathering data just doing record stuff. 10 You might want to know how many TB cases do you have 11 in your prisons, or hep C and so forth. 12 So I think the answer to your question is 13 we don't know the answer to that question yet but I 14 think we're trying to take a broad view before we come 15 to any direct conclusions about that. 16 I think I've forgotten your third 17 question. 18 MR. PALMER: I think it pertained to 19 whether or not prison authorities are receptive to 20 having more research done in prisons. And I'm not 21 talking about the quality improvement projects and 22 gathering data strictly for trying to improve the 33 1 prison conditions. 2 I guess I'm talking about researchers from 3 universities coming in, doing clinical research or 4 doing behavioral science research. Are they receptive 5 to those kinds of activities, or would they rather not 6 have people come into the prisons and do research? 7 MR. PALMER: I think that question is 8 embedded in two problems. In some states, the State 9 of California since we did the most studies there, the 10 classical clinical research that was going on at 11 Jackson Prison in Michigan, you can't do in 12 California, because there's a statute that says, "Thou 13 shall not do any bio-medical research." That's on one 14 hand. 15 On the other hand, people who are thinking 16 systematically about the effects of the incarceration 17 system know that most of the people in prison are 18 coming back into the community. So at the same time 19 in California and the Bay area, two of the leading 20 universities, Stanford and University of California, 21 San Francisco are starting programs in correctional 22 health. 34 1 I think the problem is that the problem of 2 maintaining the health with that population may or may 3 not be linked in some people's mind to more research 4 or access to the latest treatment. I guess I do -- we 5 don't know the answer to that, but the few people 6 we've talked to in public have said, you know, "If 7 there's a treatment available for hep C or AIDS, we 8 want our folks to have access to it and we don't want 9 to be excluded." 10 And we haven't yet -- we've heard 11 testimony from folks who want to do that, but our 12 report, I think, will reflect what we find, 13 particularly in those surveys, because our surveys 14 started off to just be a few states. But we frankly 15 expanded it to do an email survey of a large number of 16 states. So we'll have some data about people's 17 attitude or what they are willing to describe to us. 18 DR. PRENTICE: Okay. Susan. 19 MS. KORNETSKY: One of the things that 20 came up with our initial discussions was really also 21 centered around the definition of prisoner. You've 22 really limited your comments to those behind bars, but 35 1 there was lots of discussion about the regs as they 2 currently are written in people who have their rights, 3 civil rights removed but may not be behind prison bars 4 -- even juvenile detention homes and stuff like that. 5 Sorry about that. 6 So I guess I'm questioning how -- I mean, 7 I know you can't talk about the report itself, but is 8 that being taken into consideration? 9 MR. PALMER: Yes. We have spent a lot of 10 time talking about the definition of prisoner and 11 whether or not that needs to be expanded or changed in 12 light of conditions and trying to understand how the 13 National Commission may have arrived at their 14 definition. We had -- at our last meeting, had a 15 report -- Judy, I believe -- that explained -- we got 16 some data about how many folks or how many projects 17 are actually in halfway houses or jails or people on 18 parole and so forth. 19 So we are addressing. That's a subpart of 20 the larger question. We will answer that question or 21 give our best guess as the best way to answer that 22 question in our report. I'm sure of that. 36 1 DR. PRENTICE: Susan. 2 DR. WEINER: This is really a point of 3 clarification. Is the committee covering or 4 discussing private prisons? And I'm not sure about 5 the jurisdiction of those prisons and if those prisons 6 are used more or -- if they differ from the state 7 prisons, that if they -- if companies are more engaged 8 in doing research in those settings than in others. 9 MR. PALMER: We have had some discussion 10 about that. I think -- I'm not on the survey part of 11 the data committee; I'm on another workgroup. We 12 divide ourselves into workgroups at this point. But 13 I know we've discussed that issue. Speaking as 14 someone with legal training, the contracting out of 15 the prison function has been litigated in some small 16 places. There have been some questions about what 17 happens. 18 And I think my preliminary -- this is only 19 myself speaking -- my preliminary notion is prisoners 20 are strange in the following sense, in that the only - 21 - people in this country say you have a right to 22 healthcare. What they mean is if you show up at the 37 1 emergency room injured, someone will take you in and 2 then figure out if you can pay for it. 3 There's been litigation over time that has 4 established that once you have someone under state 5 custody, you have to provide at least a minimal amount 6 of healthcare. So the irony is prisoners have 7 actually a legally enforceable right if they can find 8 a person to bring suit to the healthcare. If that's 9 true, speaking only as a former law professor, you 10 cannot contract away that obligation. 11 So on the healthcare side, no. But that 12 does not answer the question of whether or not more 13 research might be going on because of that. We don't 14 know that and we'll see if -- what our data tells us. 15 One thing we will do is we will very clearly tell you 16 what we haven't done. 17 If we are not able to find the information 18 like that, our report will reflect we couldn't do 19 that; we didn't have the folks or we didn't have the 20 time. Our goal is to give you something that's useful 21 to start the process that you want to start here. 22 And if we can't answer that question -- 38 1 I'm pretty sure we'll have data on the percentage of 2 people in state facilities and we hope to gather some 3 notion of how many folks are in these contracted 4 private corporations. 5 DR. PRENTICE: Felix. 6 DR. GYI: Professor Palmer, thank you. I 7 found that to be a fascinating process that you're 8 going through. And just from a personal perspective, 9 I really began to appreciate the application of the 10 principle of justice when you started to unravel this 11 particular discussion. And so I'm encouraged to hear 12 you say that you're taking a more humanistic approach 13 as opposed to a more regulatory or legalistic approach 14 to help us to identify some of these issues. 15 One of the things that we've had to 16 grapple with are differences between federal 17 regulations and state regulations, and you started to 18 allude to that. Will your committee also be looking 19 at and giving us some recommendations on what some of 20 the thorny state concerns might be so that as we look 21 at prisoner research, including what constitutes 22 incarceration, we can have a better handle and 39 1 direction on how we might approach that on a state-by- 2 state basis? 3 MR. PALMER: I think we are looking at 4 that. I think we are -- we will answer your charge 5 which would help you, but in all IOM reports they are 6 also other things, issues that might need to be 7 studied. I think we are trying to at least think 8 about these problems systemically. We're not looking 9 at it -- we're not going to do your job of writing the 10 regulations. 11 We're going to try to give you a framework 12 so if you write the regulations, you'll be aware of 13 their impact or lack of impact in some areas that 14 might be of concern to you, and some guidance as to 15 who can help in that process of resolving those 16 issues. But we were lucky -- we're lucky; some of the 17 folks on my committee, as you think back to it, have 18 extensive work in the prison system in Texas, 19 California, people from New York. 20 We've got the big states -- the big bulk 21 of the prisons. We've had presentations from people, 22 from the federal bureaus, and they have slightly 40 1 different regulations. So we're getting a good -- 2 we're getting out there, trying to get a good feel for 3 what's going on. 4 And I think our email survey will give us 5 some in-depth questions as to what's happening in 6 Tennessee, for instance, where they might have more 7 private prisons than a place like California that has 8 none -- or privately run prisons. I think it's a 9 contradiction to say it's a private prison. It's 10 contractually run prisons. 11 DR. PRENTICE: Celia. 12 DR. FISHER: Thank you also for your 13 presentation. I think part of Ernie's questions 14 touched on this, but a lot of our discussion on 15 Subpart C had to do with transitioning from having 16 research approved under Subpart A or Subpart D, and 17 then -- in other words, you are studying somebody 18 outside of the prison system, and then all of a sudden 19 they're incarcerated. And then all of a sudden, you 20 have to take them out of the research and have a whole 21 different review board to come under Subpart C. 22 Well, there seem to be some protections 41 1 put in place for when such individuals are receiving 2 medical treatment. And I don't even know if those 3 provisions are clear to ensure the continuity of their 4 receiving medical treatment if they were receiving it 5 outside of the prison as part of a research protocol. 6 But especially for social behavioral sciences, there 7 didn't seem to be any mechanism of continuity. 8 So although you may not be -- your 9 committee may not be making specific recommendations 10 about regulations, I think it would be very helpful to 11 us to be looking at how existing requirements among 12 the different subparts of A, B, C and D are hampering 13 or not protect -- are hampering research or failing to 14 protect prisoners in any way. So I hope that you're 15 going to be looking at those transitional kinds of 16 issues. 17 And the second point I'd like to make is 18 you raised an interesting question about quality 19 assurance. And once again, I think that is something 20 that is very confusing at the moment across the board, 21 whether or not it's in prison research or not, as to 22 whether or not that's research. I guess I would 42 1 propose a caveat and then also ask for your 2 committee's help. 3 A caveat is that we do not want prisoner 4 research like any other research to be able to be 5 conducted under a guise of quality assurance because 6 that will be an easy way out in some sense from these 7 very difficult issues. At the same time, quality 8 assurance is critical for any institution to be 9 operating. 10 So beginning to try to tackle at least 11 examples within the prison system of what you consider 12 quality assurance versus research may be helpful for 13 the broader discussion that we're going to have to 14 have on those issues. 15 MR. PALMER: I agree with you on your 16 first issue. The transition issues that have been put 17 before us and are trying to think -- our report will 18 try to think through those issues very carefully. And 19 the second issue that you've raised about the 20 loopholes that we could create if we were too anxious 21 to put everything under one rubric, I think that's 22 going to be addressed too, because I think we're 43 1 trying to also get a sense that we may have created 2 loopholes in the present system, too. 3 You may force people to call something 4 evaluation that they really would like to see as 5 research because a limitation for instance that it's 6 got to be published, that may have been a notion in 7 1976, but that's not the only way people share data in 8 our own lives today. So we're going to try our best 9 to address both of those issues. 10 DR. PRENTICE: I guess I can have the last 11 question. I want to take up where Felix began on the 12 issue of justice. The genesis of the National 13 Commission's recommendations on research involving 14 prisoners which ultimately culminated in Subpart C, as 15 you know better than I, is based upon the fear that 16 prisoners were being exploited. 17 You go all the way back of course to the 18 Nazi doctors' trials at Nurenberg, Jessica Mitford's 19 book, where there's the quote "Cheaper than 20 chimpanzees." The pharmaceutical companies having 21 laboratories set up in many of the nation's prisons. 22 So the idea was, if you are a prisoner, you are in an 44 1 environment that is inherently coercive, and therefore 2 you are being coerced into participating in research 3 and we need to restrict that research. 4 And we've done a very good job of 5 restricting research as evidenced by California; you 6 can't do any clinical research in California prisons. 7 So now that there is an IOM study ongoing and you've 8 gone around the country, and you have had hearings and 9 you had a lot of testimony, what is the general 10 attitude that you've seen from former prisoners, such 11 as Edward Anthony who was at the Holmesburg Prison; 12 current prisoners; and prison authorities? 13 Do they say, "This is an issue of justice. 14 We need to be able to provide opportunities for 15 prisoners to participate in research for the benefit 16 of both themselves and other prisoners? Or are you 17 encountering resistance and saying, "You know, this 18 should not happen. This is going to be re- 19 exploitation all over again"? 20 MR. PALMER: I think we've heard 21 conflicting reports on both sides. Some folks who are 22 worried about the exploitation; some folks, I think 45 1 some of the prisoners we've talked to, particularly at 2 Vacaville, felt they are competent to make those 3 decisions. 4 I think the panel -- I think the 5 exploitation -- frankly, we're a little bit 6 bureaucratic that we're worried about is that the 7 prisoner panel that we might be using then a window 8 dressing. 9 And therefore, we've got -- they're going 10 to try to deal with that problem. I think we're 11 hearing the tension right now, and I think that's part 12 of a larger tension. In the literature, I think 13 Hastings Center report had the recent issue this fall 14 has a whole discussion of confusion about coercion and 15 so forth. And we're hoping that our report can deal - 16 - we feel that ethical framework or suggesting an 17 ethical framework, we will take account of that issue. 18 We have a paper coming in on re-looking at 19 the question on justice because one of our early 20 readings, Professor Pat King, I think was the name of 21 the Commission, raised that question for us in a very 22 dramatic way of, "Is prisoner research a question of 46 1 justice, not a question of coercion?" And how do you 2 deal with that in a systemic fashion? We have not 3 made up our minds, but there's been lots of discussion 4 about that question. 5 We don't want a regulatory system that 6 inhibits progress, but you don't want to reopen the 7 door. And I know publicly a number of prisoners have 8 said, "We don't want bio-medical research of the 9 previous kind allowed back in prisons." That doesn't 10 mean -- here, also, the feeling that if you're going 11 to do a clinical trial for the best treatment of 12 something that's very prevalent in prison, we might 13 want to participate. 14 I remember very clearly the four gentlemen 15 we were talking to in Vacaville saying, "I know what 16 the rules are here. If you tell me something 17 different than the rules, I'll dismiss you because I - 18 -" You know, what is a prison? The only person we 19 actually understood was Sidney (ph). He'd been there 20 for 31 years, and he didn't look much older than I 21 was. He had spent most of his adult life in prison. 22 And when you talk to these folks, you know 47 1 they're very intelligent and so forth. The one part 2 we haven't quite -- the big issue, though, that we 3 just heard on was a public meeting, is because of the 4 cycle of people going in and out of the system, 5 prison, some of the mental health issues in prisons 6 might create some different things to think about. 7 So the healthcare might not just simply be 8 do you have enough treatment for AIDS; it's, are you 9 really giving people sufficient opportunities to deal 10 with their problems so that when presented with an 11 issue, they're not -- you're fairly sure that they 12 have opportunities to deal with the underlying issues. 13 The American Psychiatric Association 14 presentation that I recently -- claimed the biggest 15 mental health treatment system in the country are 16 prisons right now. That's their position; that's 17 their public position, and we're trying to listen to 18 that against people who are psychiatrists who have 19 done a lot of research in various prisons and 20 testified in a lot of the litigation that's gone on in 21 the past few years, 15, 20 years, on those issues. 22 DR. PRENTICE: Okay. Thank you very much. 48 1 Let's give him a hand. We look forward to your report 2 hopefully in the spring. Hopefully. Okay. 3 We now have an update of the FDA/OHRP 4 Joint 407 Review Process. And both Sara and Kevin are 5 here. And the two individuals who are going to 6 present are Dr. Sara Goldkind and Dr. Kevin Prohaska. 7 Do I pronounce that name right? Prohaska. 8 Now, let me tell you a little bit about 9 both of them. Sara is the bio-ethicist in the Office 10 of Pediatric Therapeutics within the Office of the 11 Commissioner of the FDA. She's board certified as an 12 internist and completed a fellowship in clinical 13 medical ethics at the University of South Florida 14 School of Medicine, which is where I graduated from 15 actually way back in God knows when, long time ago. 16 And you were on the faculty within the Department of 17 Medicine. She also has a masters in religious 18 studies, focusing on comparative religious ethics and 19 public policy. 20 And I will read you Kevin's bio. 21 Commander Kevin graduated with honors from Des Moines 22 University, College of Osteopathic Medicine in 1987. 49 1 He's board certified in family medicine, and has a 2 diverse background that includes academic, clinical, 3 military and regulatory medicine. He was in private 4 practice in Chicago, had academic appointments in 5 Chicago and California; military service in Germany 6 and Kuwait. 7 He spent five years with the Food and Drug 8 Administration as the medical review officer of the 9 Division of Neuropharmacological Drug Products. And 10 currently, he's working with OHRP, Division of Policy 11 Assurances, and he functions as the Children's 12 Research Coordinator for the Office, so that's your 13 subcommittee, Susan and Celia. He has the U.S. Army 14 meritorious service medal award for U.S. Army 15 commendation medals; U.S. Public Health Service Corps 16 combination medal; the Secretary's recognition award 17 for heroism and volunteerism. Those are all those 18 medals that are on his chest over there. 19 And we appreciate you taking the time to 20 come and talk to us. We're looking forward to an 21 update. As you know, one of the recommendations that 22 came out of the 407 review work that Celia and Susan's 50 1 committee did was we would like to have an update, 2 progress report every year, given to us at SACHRP. So 3 this is your opportunity to give us that update. 4 UPDATE OF FDA/OHRP JOINT 407 REVIEW PROCESS 5 DR. PROHASKA: Well, thank you very much 6 for that introduction. And the ribbons can be had for 7 about a dollar apiece at the uniform shop, so if 8 anybody's interested just let me know. 9 Well, first of all, I'd like to thank you 10 for this opportunity to update the committee on the 11 recent changes to the 407 review process. To start, 12 I will discuss the 407 review process and how it has 13 changed since SACHRP has issued its recommendations in 14 the Spring of 2004. 15 This review will not include specific 16 details about each previous 407 panel that existed in 17 the past, but rather may touch upon the general 18 lessons that were learned from the reviews. My 19 presentation will be followed by Dr. Goldkind, who 20 will discuss how well the 407 process is working since 21 the recommendations have been enacted. And finally, 22 we'll finish with a question and answer session. 51 1 Just as a matter of review, what we're 2 talking about is the area of the regulations commonly 3 known as Subpart D, and these are additional 4 protections for children that are involved in 5 research. And as you know, they were adopted in 1983. 6 And specifically, we're talking about the 7 regulations found at 46.407 which the IRB cannot 8 otherwise approve by under a 404, 405 or 406; however, 9 they feel it presents an opportunity to understand, 10 prevent or alleviate a serious problem affecting the 11 health or welfare of children. 12 This particular regulation requires that 13 a board of experts, a panel of experts be convened in 14 which they give recommendations to the secretary 15 relative to the determination that needs to be made 16 ultimately as to whether or not to support the 17 proposed research. 18 Just as a matter of looking back to 19 previous 407 panels that have existed, the first panel 20 occurred in January of 1999. And between '91 through 21 November of 2002, there were 12 panels all of which 22 were closed. Closed meaning that they were not open 52 1 to the public for public scrutiny as much as the 2 panels are today. Of those 12 panels, five were 3 withdrawn, four were approved by HHS with 4 stipulations, and three were disapproved by HHS for 5 funding. 6 Oddly, one particular panel was a virtual 7 panel, meaning that the panel actually did not convene 8 in a centralized location, but rather reviewed the 9 materials on their own in a period of time, in a 10 period of a month, and then gave independent reports 11 to OHRP. All the panels, as I said, were not open to 12 the public, although public comments were sought 13 through Federal Register notices. 14 The five withdrawn studies were either re- 15 categorized by the IRBs as 404, 405s or 406, or were 16 closed to enrollment. The three that were disapproved 17 were disapproved in part to an apparent lack of 18 justification for doing the study in children prior to 19 doing it in adults. The virtual review was conducted 20 on the Drivax study, which proposed to evaluate the 21 clinical safety and immune response to smallpox 22 vaccine in children. 53 1 The first panel in 1991 took seven months 2 from the time that the request was submitted until the 3 issuance of the HHS determination letter. Thereafter, 4 the duration of time increased significantly. Some of 5 the lessons that I believe were learned from these 6 panels, although I was not presently involved with the 7 process at the time, was that there was need for clear 8 guidance from OHRP on what is requested in a 9 submission. 10 Several of the submissions were delayed 11 because there was a lack of sufficient information 12 provided by the IRB relative to the type of 13 deliberations they had or the updated consent forms 14 weren't provided, a lot of different problems of that 15 sort. There was also a need for harmonization between 16 OHRP and FDA. The private investigators and the IRB 17 chairman's presence was helpful at the panel meetings. 18 Previously, this was not requested. And as you know, 19 it is nowadays. 20 Also, there was an apparent need for more 21 transparency in the process and more input from 22 subject advocates. And finally, there was a need for 54 1 a standardized 407 process. In the past, each panel 2 was slightly different from each other. 3 So the early panels were often 4 unstructured, which had no votes, no minutes, no 5 transcripts, no public participations. The panelists 6 were promised anonymity and individual reports were 7 created. No consensus report was created, and that 8 often was problematic. This whole process was 9 redefined by SACHRP with a greater emphasis on 10 openness and structured meetings. 11 The SACHRP's recommendations were 12 forwarded to the secretary on July 8, 2004. The 13 secretaries responded in an affirmative manner in 14 December 29, 2004, and OHRP issued guidance in May of 15 2005. So it was a relatively quick process once there 16 was agreement to it. 17 The key recommendations that SACHRP 18 forwarded and OHRP instituted with the help of the FDA 19 including a requirement that OHRP screen all requests 20 and provide guidances to the institution. OHRP does 21 the initial screening, which permits the opportunity 22 to detect and return any deficient application to the 55 1 IRB for further consideration under 404, 405 and 406. 2 There was also the recommendation that the 3 process be open, and the open process was to include 4 more public participation and a greater emphasis on 5 posting materials on the web for public review. The 6 panelists' discussions were to be governed by a 7 structured process with votes, a chairman, proper 8 transcripts and so forth, and a consensus report, 9 which was available to -- which would be made 10 available to the public. And the panelists of course 11 were no longer to be anonymous. This was supposed to 12 be an open process. 13 And finally, there should be a greater 14 emphasis on subject advocacy. And also, the final 15 issue is to monitor the 407 process. So taking into 16 consideration SACHRP's recommendation, OHRP developed 17 and issued guidance which is available in the meeting 18 package, but which is also available on our website 19 under the children's page. And that was issued on May 20 26, 2005. 21 The guidance document outlines the 22 necessary IRB findings to justify the 407 review 56 1 request. It also outlines the steps in submitting a 2 package; the OHRP possible response to a request; and 3 details about the review itself and possible outcomes 4 that can come from the panel of experts and the 5 secretary's determination. 6 An update of all -- also, OHRP was -- it 7 was recommended that they update the SRIC and SACHRP - 8 - which we do. THE SRIC is updated on every meeting, 9 and SACHRP is updated yearly, this being the first 10 update. 11 I won't go over these all in quite detail, 12 but this is directly from the guidance, and these are 13 all the various items that need to be submitted by the 14 IRB or the institution relative to a 407 request. 15 These are the standard information that we need on all 16 407 requests. After receipt, it may be determined 17 that certain specific items might be needed and that 18 will be requested prior to any 407 panel. 19 Relative to the process itself, as 20 recommended by SACHRP, OHRP does the initial 21 assessment to determine if sufficient materials have 22 been provided and the appropriate findings by the IRB 57 1 have been made in order to convene a 407. Once this 2 is done, or actually in tandem to this, all materials 3 submitted by the IRB are immediately forwarded to the 4 FDA upon receipt so that they may determine if their 5 regulations apply. 6 And then if the FDA regulations do apply, 7 OHRP has delegated its authority to the FDA to convene 8 the panel. However, although OHRP has delegated its 9 authority to convene the panel of experts, OHRP has 10 frequent consultations with the FDA in order to 11 facilitate and stay engaged in the process. 12 Talking further about the process itself, 13 once those initial steps are done, OHRP notifies the 14 funding agency and asks for any peer review that was 15 done, if done. The panel of experts is then 16 identified. For this, we try to strive to have at 17 least two public members which exceeds SACHRP's 18 recommendations for at least one. We work closely 19 with the FDA on this process as well. OHRP requests 20 written permission from the IRB and the PI to post all 21 relevant material on the web for public review. 22 The FDA publishes the Federal Register 58 1 notices of the meetings and notice soliciting public 2 comments, the goal being at least 30 days for a 3 comment period. And the meetings are located here in 4 the Washington D.C. area. And then concurrent with 5 the Federal Register posting, OHRP and the FDA post 6 all relevant material on their websites. 7 Ultimately, when we finally have the 8 meetings, the meetings are open to the public. The 9 Pediatric Ethics Subcommittee, which is an FDA 10 subcommittee of the Pediatric Advisory Committee, is 11 open to the public and the chair of that committee 12 creates consensus reports which he or she presents to 13 the Pediatric Advisory Committee, often the very next 14 day. So it's an awful lot of work to do all at once. 15 The Pediatric Advisory Committee makes 16 recommendations to the Food and Drug Administration 17 Commissioner which ultimately gets transferred to OHRP 18 through the Office of the Pediatric Therapeutics. 19 When available, all transcripts are then posted on the 20 web. 21 After that, the FDA Commissioner member 22 with recommendation is forwarded to OHRP. Once it 59 1 comes to my desk, I vet it through the various people 2 in my office. We review our own personal minutes and 3 we either concur or disagree in consultation with the 4 FDA. And all of the recommendations including the 5 Commissioner's memo, OHRP's recommendations are 6 forwarded to the assistant secretary of health for 7 determination. 8 All the way through this process, all 9 relevant parties, all stakeholders are kept informed 10 of the status and the findings as they are. Now, if 11 the Secretary's determination is that the protocol 12 should proceed after modification, which is generally 13 the majority of the recommendations to date, the 14 investigator must modify the research proposal, 15 parental permission and assent forms and other 16 documents as appropriate and submit the revisions to 17 the IRB for review and approval. 18 Once that is done, the IRB or other 19 appropriate institution officials must then submit the 20 approved revised documents to OHRP for final 21 concurrence before the research can proceed with 22 funding. Close out actions at OHRP will do once that 60 1 material is received is review the material, of 2 course, and then either concur or disagree, and then 3 will post the final findings and then will inform all 4 relevant parties of the final determination. 5 Since the process has been redefined, 6 there have been two open panels completed, both of 7 which were joint OHRP/FDA panels. We suspect that in 8 the future, the vast majority of them will be OHRP/FDA 9 panels. And then there's one pending, which will be 10 occurring within the next two weeks. 11 The first one was in September of 2004, 12 which was the effects of a single dose of 13 dextroamphetamine in ADHD. And that particular panel 14 had recommended that the protocol be approved with 15 stipulations; however, that was later withdrawn due to 16 some safety concerns that came up after the panel met. 17 Then in June 2005 was the second of the joint panels, 18 and that was a precursor preference in surfactant 19 synthesis of newborns. The determination is pending 20 on that one, the final determination. 21 And then finally, we have one coming up in 22 November, which is going to be reviewing a research 61 1 protocol entitled, gonadotropin releasing hormone 2 agonist test in disorders of puberty. 3 DR. GOLDKIND: Thank you very much for the 4 opportunity come and speak to you about this, what we 5 think is an extremely important process for the 6 advancement of pediatric research. The FDA adopted 7 the Subpart D regulation in 2001, so we have had to 8 date eight referrals under the -- what we call 50.54, 9 which is akin to HHS 407. 10 Of those, only four have gone through the 11 process, or will go through the process as Dr. 12 Prohaska mentioned, in a couple of weeks. And all of 13 these that the FDA has had go through the process have 14 been shared with OHRP. So we have a much more limited 15 experience with the Subpart D process. Ours has been 16 predominantly since the formation of the Pediatric 17 Advisory Committee which was legislated in December of 18 2003. And that legislation giving us the full 19 Pediatric Advisory Committee also enabled us to form 20 the Pediatric Ethics Subcommittee which represents our 21 expert panel. 22 So what I wanted to do is to go over where 62 1 are we today, having looked at our new process since 2 December of 2003. And the FDA has embraced many of 3 the recommendations that SACHRP made in an overarching 4 manner related to timeliness and efficiency and 5 openness and harmonization between the two federal 6 agencies. And you'll see reflected in this process 7 our -- you'll see reflected in this process our manner 8 of accomplishing some of those overarching principals. 9 We think this is -- we have now achieved 10 a truly open process. We post, as was mentioned, a 11 Federal Register notice requesting written comments. 12 Those written comments are if at all possible -- if 13 they're -- if it's few enough for us to be able to 14 replicate in total, those are all replicated in total 15 for the panel members, both the Pediatric Ethics 16 Subcommittee and the Advisory Committee. They are 17 also summarized by the Pediatric Ethics Subcommittee 18 chair and presented for comment and review at the 19 meeting itself. 20 We also -- we allow a 30 day comment 21 period, at a minimum. We also have an open public 22 hearing at the Pediatric Ethics Subcommittee itself, 63 1 and at the Pediatric Advisory Committee. So there is, 2 we think, quite a significant amount of public 3 scrutiny and opportunity for comment. 4 All the documents relevant to the review 5 are posted ahead of time, and all the resulting 6 documents such as the Pediatrics Ethics Subcommittee 7 chair's summary of the expert panel meeting as well as 8 the Pediatric Advisory Committee chair's letter to the 9 Commissioner, as well as the Commissioner's 10 memorandum, and ultimately the assistant secretary for 11 health's memorandum are all posted on the FDA and OHRP 12 websites as well. 13 We also -- because we can have the 14 Pediatric Ethics Subcommittee, we are enabled with the 15 ability to have face-to-face meetings of all the 16 pertinent experts. All experts had the opportunity to 17 express their opinions, review all the materials and 18 listen to public comments before rendering 19 recommendations. As I mentioned, briefing materials 20 are sent in advance to the expert consultants and to 21 the Pediatric Advisory Committee members who 22 ultimately have to discuss the protocol and the Ethics 64 1 Subcommittee recommendations as well. 2 We think there's been a very close working 3 relationship and harmonization between OHRP and FDA. 4 As soon as OHRP gets a referral, they send it directly 5 onto us for us to review if there's an FDA 6 jurisdiction or regulatory authority over this 7 process. And if it's going to be a joint review, we 8 start immediately with identifying expert panel 9 members and expert speakers as well, if needed. 10 It's been a -- we have -- over the past 11 three referrals, we think we've significantly 12 streamlined the process to make it much more 13 efficient, but we do also recognize that this process 14 involves a national review and two federal agencies. 15 We've made it a much more timely process, again 16 recognizing that the Pediatric Advisory Committee 17 generally meets three times a year. 18 And so we've been -- we have to date 19 scheduled the Pediatric Ethics Subcommittee meetings 20 to occur within a very short period of time before 21 those Advisory Committee meetings so that there's a 22 quick turnaround on the presentation of the expert 65 1 panel to the Advisory Committee. 2 We at the agency -- at both agencies 3 review the applications to verify they meet the basic 4 requirements of 407 and 50.54. We've also embellished 5 this by doing a joint telephone conference with the 6 IRB chair or representative, as well as the principal 7 investigator, to not only delineate what this process 8 is for them, but also to make sure that we completely 9 understand their reasons for making the referral and 10 all the other issues surrounding that particular 11 protocol referral. 12 We, as well, during that telephone 13 conference encourage their participation -- strongly 14 encourage their participation in terms of attending in 15 person the Pediatric Ethics Subcommittee, and if 16 possible the Pediatric Advisory Committee meeting. 17 And then we are now trying to greatly 18 facilitate the information exchange between the 19 Pediatric Ethics Subcommittee and the Pediatric 20 Advisory Committee. According to FACA, at least two 21 members of the Pediatric Advisory Committee need to be 22 a part of the Pediatric Ethics Subcommittee. We've 66 1 also to date had the chair of the Pediatric Advisory 2 Committee participate in the Pediatric Ethics 3 Subcommittee as well, so that we have a facilitation 4 of information transfer from the Ethics Subcommittee 5 to the Advisory Committee, which is the ultimate body 6 that has to send the recommendations to the FDA 7 Commissioner. 8 We have also taken steps to make sure that 9 any materials that are presented to the Pediatric 10 Ethics Subcommittee are also transmitted in a timely 11 fashion for review by the Pediatric Advisory 12 Committee, so they're prepared to be able to 13 deliberate on these issues at its meeting. And we've 14 also tried to encourage the principal investigator to 15 attend the Pediatric Advisory Committee meeting. 16 And we're trying to logistically see if we 17 can make the discussion time at the Pediatric Advisory 18 Committee such that it logistically allows the PI to 19 be able to be present at that meeting, to again 20 facilitate more of an information exchange by the two 21 committees. 22 We think that this process at this point 67 1 greatly contributes to pediatric research, to IRBs, 2 investigators, sponsors and ethicists, and if you 3 will, in a sense, it forms case precedents for 4 pediatric research. Thank you. 5 DR. PRENTICE: Okay. Thank you very much 6 for that update. I'd like to address my first 7 question to Kevin. Kevin, when you were describing 8 the 407 review process, you mentioned reaching 9 consensus and voting. I assume that you're not 10 talking about a solo 407 review process; you're really 11 talking about the joint 407/54 review process. Is 12 that -- 13 DR. PROHASKA: That's correct. Yes. 14 DR. PRENTICE: Okay. That's what I 15 thought. 16 Sara, you mentioned that since 2001 when 17 FDA adopted Subpart D as the interim final rule, 18 you've had eight -- you referred to it as referrals. 19 Four have gone through the process. I guess this is 20 my question: since 1991, and Kevin indicated this in 21 his presentation, there have been 12 closed panels. 22 The children's regulations were issued in 1983, so 68 1 between '83 and '91, Kevin, I assume, and I'm going to 2 get to my question for Sara in a moment, I assume 3 there were no panels. 4 DR. PROHASKA: That's correct. 5 DR. PRENTICE: Okay. So clearly, either 6 nobody understood what Subpart D was or we simply 7 didn't do any research that would qualify for 407, 8 right? 9 DR. PROHASKA: That's correct. Actually, 10 all through the 90s there were only two panels, and 11 it's accelerated since 2000. 12 DR. PRENTICE: Exactly. That's what I 13 thought. 14 DR. PROHASKA: So even during the 90s, 15 there wasn't a great appreciation for the process. 16 DR. PRENTICE: Would you care to 17 speculate why it accelerated since 2000? 18 DR. PROHASKA: I plead the Fifth. I'm 19 afraid I don't know. 20 DR. GOLDKIND: I can speculate a bit. I 21 think that one reason is that certainly the process is 22 becoming much better known. I think another reason is 69 1 that in 1997 FDAMA was passed and that had legislative 2 stipulations regarding pediatric exclusivity which 3 really catalyzed to a great extent pediatric research. 4 DR. PRENTICE: Okay. And there's probably 5 some other reasons as well. 6 DR. PROHASKA: If I may also add that I 7 think there's a greater awareness today that there 8 needs to be more research in children. That's 9 something that is a growing trend around the country. 10 DR. PRENTICE: Okay. And now I'm getting 11 to my question I started off asking Sara. It took the 12 academic IRB community, i.e. academic health science 13 centers, a long time to come to grips with Subpart D, 14 as evidenced by the data. 15 For a variety of different reasons, we 16 really didn't understand we couldn't apply Subpart D 17 appropriately. We were probably classifying projects 18 as 405 or perhaps 406 that didn't really qualify. And 19 we've begun to change that because of this awareness. 20 However, there are something like 3,000 to 21 4,000 IRBs out there; nobody seems to know the exact 22 figure. They review FDA regulated research. They 70 1 review FDA regulated research that involves children. 2 They are subject to Subpart D. It's my feeling that 3 there are hundreds and hundreds of IRBs out there who 4 do not have a grasp of Subpart D -- how to interpret 5 it, how to apply it. And if that is indeed the case, 6 are there projects out there involving children that 7 should be referred for a 54 review that are not? 8 That's one question. 9 The second question would be: when the 10 FDA reviews an IND, is there some sort of check system 11 where the FDA could say, "Hey, this is really a 54 12 project"? Those would be my two questions. 13 DR. GOLDKIND: Well, I would agree in 14 terms of your first question with the fact that I 15 think that many IRBs don't understand Subpart D. I 16 think that's been borne out in some of the literature 17 and certainly in informal conversations, as well as in 18 inquiries, as well as ethics meetings and PRIM&R 19 meetings. 20 In terms of the second part of your 21 question, the reviewers -- we're working internally to 22 make reviewers more cognizant of specific issues that 71 1 they need to consider when they're reviewing pediatric 2 trials. And we also, at the agency, have the Division 3 of Pediatric Drug Development within CDER which is a 4 consultative division in the Office of Pediatric 5 Therapeutics which I'm a part of in the Office of the 6 Commissioner. And additional centers are forming 7 special pediatric working groups to try and make 8 reviewers much more aware of pediatric issues. 9 DR. PRENTICE: Okay. Thank you. Celia 10 and Susan, you get first shot now because it's your 11 work that led to these -- implementation of these 12 recommendations. 13 DR. FISHER: It sounds to me like good 14 news. It sounds like the harmonization process is 15 working. I know Susan and I have looked at the 16 website. It seems clear to us what the rules are in 17 terms of how it's written out. I don't know if it's 18 the purview of our committee, but how to more greatly 19 publicize to IRBs that that guidance is now out there, 20 I think is very important. 21 I thought the contribution -- one of the 22 most significant contributions of what we were able to 72 1 do was the educative process for the IRBs so that 2 hopefully they wouldn't be as fearful to either 3 approach some research as 407s, or at the same time, 4 if they did, that OHRP now had very specific processes 5 that IRBs could understand for providing feedback 6 about why what they were suggesting was not a 407. 7 So I think the process looks very good. 8 And it sounds like what you're saying, Ernie, and I 9 agree, is how do we get it to be more widely used? It 10 doesn't necessarily mean that there will be more 407s. 11 In fact, by clarifying what a 407 is, it may mean that 12 we don't see as many 407s. So I don't think the 13 outcome measure that will evaluate the success of what 14 was done is necessarily in increase in 407s. 15 DR. PRENTICE: I guess along those lines, 16 perhaps -- excuse me a second, Susan. Kevin, have you 17 had submissions which are -- where OHRP has said, 18 "It's not a 407" and you've turned them back? 19 DR. PROHASKA: Yes. Well, actually, yes, 20 we have. We've had a single one that was submitted 21 that on initial screening, and after vetting through 22 various people in my office, we all concurred that the 73 1 materials that were submitted were inadequate. There 2 wasn't adequate consideration of various Subpart A 3 type of issues, so we sent it back for further 4 consideration. 5 But then also to answer your question, or 6 your comment rather, relative to distributing the 7 guidance, it's my understanding that a listserve 8 message went out to all the various IRBs that are on 9 our listserve so that they were notified that the 10 guidance was available. 11 Plus we have outreach programs including 12 meetings that we attend, including the upcoming 13 December meeting in Boston for the PRIM&R. There will 14 be a discussion on 407s. So we are out there trying 15 to educate the various IRBs on the process. 16 DR. PRENTICE: Susan. 17 MS. KORNETSKY: I think we all recognize 18 that this was a first step with trying to sort out the 19 children's regulations. I think hopefully if our 20 definition piece goes through in terms of to guidance, 21 that that's going to also relate to this because that 22 will define what minimal risk is, benefit. So my 74 1 expectation is that there may be more that develop out 2 of that, but I think that you're geared up now to do 3 that. 4 And I know that frequently now I get 5 calls, and I know of one that is coming your way if it 6 hasn't already because I was called right before I 7 left, when institutions are contemplating and saying, 8 "This is a 407" and wanting to talk a little bit about 9 it. I often get called just a little bit about the 10 process. So I think it's working, but I think the 11 second step, which is as important, is the definition 12 piece. 13 DR. PRENTICE: Ada Sue. 14 MS. SELWITZ: I would like to 15 congratulate Sara and Kevin and FDA and OHRP. I think 16 clearly you succeeded in harmonizing the review 17 process and the process is more thorough, it's more 18 timely, and it's more transparent. And I thought this 19 was really encouraging to see this kind of 20 harmonization. And if we can just get this in adverse 21 events. But really, truly, congratulations. This is 22 excellent. 75 1 DR. PROHASKA: Thank you. 2 DR. GOLDKIND: Thank you. 3 DR. PRENTICE: I would like to also expand 4 upon Ada Sue's comments. There have been obviously a 5 number of committees that have looked at the ethics 6 and regulation research. NBAC, NHRPAC, they've done 7 great work. We've worked very hard on SACHRP since we 8 were first appointed, and the first indication of the 9 fruits of our labor is literally the 407/54 review 10 process. 11 We sent a letter to the secretary. The 12 secretary accepted it. It was passed down to OHRP and 13 FDA. And the process is now in place. 14 We have sent other letters to the 15 secretary, which we are optimistic that those 16 recommendations will also be accepted by Secretary 17 Leavitt. He passed down to OHRP and we're hopeful 18 that those will be implemented as well. It's all well 19 and good for advisory committees like SACHRP to sit 20 around here and deliberate about what we ought to do 21 and what we shouldn't be doing and we need this and we 22 need that, and we need to harmonize; but, you know, if 76 1 our product, if our work product does not get 2 implemented, then all of our efforts are for naught. 3 So I feel the same way that Ada Sue does. 4 I want to congratulate OHRP and FDA because you've 5 solved the problem that we brought to your attention, 6 and you've done it well, and we're very pleased. And 7 I would like to see the rest of the problems we're 8 addressing also be resolved in the next -- I'm not 9 going to say millennium -- in the next perhaps couple 10 of years. 11 Felix, you want to say something? 12 DR. GYI: Just a point of clarification 13 question. After the 407 review process takes place 14 and the project is approved, does that go back to the 15 local IRB? Could you help me to understand what 16 happens as a next step? 17 DR. GOLDKIND: From the FDA's perspective, 18 it goes back to the local IRB to make sure that the 19 appropriate changes have been made and the informed 20 consent documents and the protocol. I'll let Kevin 21 speak to the OHRP's vantage point because it is a 22 little bit different. 77 1 DR. PROHASKA: Let me see if I understand 2 you correctly. Do you mean approved with required 3 modifications or stipulations? Okay. In that 4 particular case, what happens is once that 5 determination is made, the information goes back to 6 the IRB and the PI. The PI is obligated to make the 7 appropriate changes, submit those to the local IRB, 8 and then the IRB after reviewing them and agreeing or 9 concurred, needs to forward them back to OHRP for 10 concurrence. And then once that concurrence is made, 11 then the funding institute -- the funding agency is 12 notified and the PI and the IRB is also notified of 13 concurrence. 14 DR. GYI: And on an ongoing, moving ahead 15 basis, how does that oversight occur? Does IRB then 16 communicate back with you and make sure that some of 17 the issues that they're facing are addressed 18 appropriately? 19 DR. PROHASKA: Yes. The IRB is welcome to 20 contact us at any time, at any point, about any 21 questions they have. Our stipulation, our requirement 22 is that the stipulations be met. The recommendations 78 1 are optional, of course, but the stipulations need to 2 be met prior to us agreeing to have the funding agency 3 release any funds. 4 DR. GYI: So the continuing review process 5 is handled on the local -- 6 DR. PROHASKA: That's correct, yes. 7 DR. PRENTICE: Susan. 8 MS. KORNETSKY: I have one more question. 9 Maybe it just slipped my mind. The recommendations 10 that come back from the secretary, I know there was 11 discussion about certainly they go back to the 12 investigator and for the institution to take care of. 13 Is that also made public? 14 DR. PROHASKA: That's correct. Yes, they 15 are. 16 MS. KORNETSKY: So that's not -- that goes 17 under the documentation of the 407 -- 18 DR. PROHASKA: That's correct. That's 19 placed on the website. 20 MS. KORNETSKY: That would be -- because 21 you talked about the case-based approach. I think 22 that's essential that IRBs realize that they can look 79 1 that up after to see the types of things that were 2 considered 407, what the stipulations. So good. 3 Thanks. 4 DR. PRENTICE: Anything else? Bern, would 5 you like to make some comments, please? 6 DR. SCHWETZ: I would like to comment on 7 the role of the public, the public input. Because we 8 continue to look for serious opportunities to interact 9 with the public, not just token advertisement that 10 we're interested in having public input. And I would 11 ask Sara and Kevin if they would comment on the kinds 12 -- the number of comments we get and who they come 13 from. Do they come from pediatricians, from 14 researchers? Do they come from parents? Who in the 15 public do they come from? 16 And a question that Ernie and I would put 17 to SACHRP: how can we in the case of this joint 18 process and other processes -- how can we engage the 19 public to a greater extent so that we don't just hear 20 from segments of the public who have a real serious 21 interest in whatever we're talking about? 22 For example, other researchers doing 80 1 research on the same kind of thing that we're talking 2 about. That may be the public, but it's not really 3 the public. And how do we reach out to get a broader 4 range of public input on some of the activities that 5 we do, and specifically in research involving 6 children? 7 DR. PROHASKA: Well, I'll try to take a 8 stab at that, if I may. First of all, the type of 9 comments that we're getting and the nature of the 10 comments that we're getting from the Federal Register 11 notification, it's the full spectrum. We're getting 12 them from people from the universities; we're getting 13 it from people from associations; various interest 14 groups; we're also getting them from the general 15 public. 16 So there are a lot of questions coming 17 that way. Now, the number of questions that come in 18 for the various 407s varies considerably between 19 protocol to protocol, so it's hard to comment on that. 20 Also, the other aspect of public comments is brought 21 in by the fact that we have subject advocates and 22 patient advocates brought into the 407 panel itself. 81 1 So that's another way that we pull in public comments. 2 Now, how to reach out to other sectors of 3 the public, that's a difficult one, because most 4 people aren't aware of the type of research that's 5 going on in children, and may or may not be interested 6 once they hear about it. But that's not an easy thing 7 to do. 8 DR. PRENTICE: Yes, Susan. 9 DR. WEINER: The best route to getting 10 feedback is really through organized parents' 11 organizations that are disease specific. And there 12 are -- I mean, it's a labor intensive effort, but 13 there are lists of those, they have websites, et 14 cetera. So that's a sort of mini-project as it were, 15 if you -- if OHRP or FDA is really interested in 16 broadening the feedback on 407 panels or any of the 17 other issues. But those are the most -- those 18 organizations have in them the most interested as well 19 as motivated and educated parents. 20 DR. GOLDKIND: Ernie, could I comment to 21 that as well? 22 DR. PRENTICE: Yes, please. 82 1 DR. GOLDKIND: Just to give you some 2 figures: for the first referral that we had in 3 September of '04, we only had three comments. For the 4 second referral that we had in June of '05, we had 5 seven comments. And I agree with Kevin's description 6 of who those comments came from. 7 When we pick our subject advocates or our 8 patient advocates for the panel, Susan, we try and go 9 to those types of organizations to draw from. We try 10 and pick them not just as advocates in general, but as 11 disease specific, if you will, or issue specific, 12 advocates, if it's at all possible. So we're trying 13 to take a stab at that. 14 And the other comment I wanted to make is 15 that we're continuing to monitor this process. We 16 really -- we greatly appreciate your positive 17 feedback, but after each one of our panel meetings, 18 we, OHRP and FDA, meet and do a post-meeting wrap-up 19 and review timelines, whether we've been satisfied 20 that the appropriate information has reached the 21 various parties. And I say that in a very broad 22 sense. And so we're continuing to monitor this 83 1 process very carefully. 2 DR. PRENTICE: Okay. One final question 3 before we break. And I'm kind of curious. If you 4 have a joint 407/54 review and the recommendation goes 5 up to the Commissioner, I assume that the secretary of 6 HHS is also involved, apprised of the recommendation, 7 right? Let's say the Commissioner and the secretary 8 of HHS just disagreed. Who trumps who? 9 DR. PROHASKA: You're going to get me in 10 trouble. I would assume that -- we hope that those 11 type of differences are ironed out before any final 12 determinations are made by either party. But in 13 general, I would expect that the secretary's opinion 14 would trump the Commissioner's opinion. 15 DR. PRENTICE: Okay. 16 DR. GOLDKIND: It is such a labor 17 intensive process. First, you start with the national 18 experts who are part of the expert panel. And we've 19 tried very hard to keep the expert panel as broad as 20 it can be, including patient advocates as needed, 21 statisticians. Also looking at the regulations in 22 terms of drawing from medicine, ethics, law, 84 1 education, et cetera. Then it goes to the Pediatric 2 Advisory Committee, and on that Advisory Committee, we 3 have experts from all different backgrounds of 4 pediatrics -- infectious disease, oncology, 5 endocrinology, et cetera. 6 And so by the time it then goes through 7 the Office of Pediatric Therapeutics where we review 8 all the recommendations for the Commissioner and make 9 comment; and from there, it goes to the Office of 10 Human Research Protection where it's reviewed again. 11 And that office makes comment. By the time it gets to 12 the secretary, as Kevin mentioned, we really hope that 13 there's been so much thoughtful input and varied input 14 that we would not end up with that kind of 15 disagreement. 16 DR. PRENTICE: Bern. 17 MS. KORNETSKY: I would remind you that 18 one of the reasons we wanted to have a joint review is 19 so that we didn't have two groups of experts with 20 different opinions. And we have solved that problem, 21 and I assure you that we would do whatever we needed 22 to behind the scenes to keep from having a difference 85 1 between a Commissioner opinion and a secretary's 2 opinion. And that's why we have a lot of discussions 3 before either one makes a declaration of what they 4 think they should do. 5 DR. PRENTICE: Okay. Thanks very much for 6 the update. We appreciate you taking your time. I 7 don't know. Do you give the Feds a round of applause 8 or not? All right. We're going to take a break until 9 10:35, and then we'll reconvene. 10 (Whereupon, proceedings in the above- 11 entitled matter went off the record at 10:19 a.m. and 12 resumed at 10:46 a.m.) 13 DR. PRENTICE: Okay. Let's begin, please. 14 This session which we're running just a bit late, but 15 not too much, is titled Identification of Future 16 SACHRP Priorities. And there are certainly many 17 issues and priorities that have been discussed by not 18 only SACHRP members but also the ex officio members in 19 conjunction with OHRP. We have identified four areas. 20 Certainly the list is not confined to only those four 21 areas, but those are the four areas that rose to the 22 top, and they are international research, multi-center 86 1 studies, evidence-based practice, and exemptions. 2 And we are delighted to have some of our 3 ex officio members interact with us. And we are going 4 to take them in order. And what I would like to do is 5 have the panelists come up, and two of them are 6 already up there, to give us their presentations. And 7 then after that, they'll sit down and the next 8 panelists will come up. And when everybody's done, 9 they'll all assemble up in front and then we'll have 10 a discussion. 11 So the first issue we're going to 12 consider, topic we're going to consider is 13 international research. And they're going to have two 14 individuals who are going to present to us, Dr. Peg 15 Barrett, who is the division director, behavioral and 16 cognitive sciences, National Science Foundation; and 17 Dr. Joan Porter, the associate director of the Office 18 of Research Insight at the Department of Veteran 19 Affairs. 20 We have asked each of these groups to try 21 to confine their formal didactic presentations to 22 about 15 minutes. And we'll hold questions again 87 1 until the end. So Peg and Joan, would you please 2 proceed? 3 IDENTIFICATION OF SACHRP PRIORITIES, EX OFFICION 4 PRESENTATION 5 DR. BARRATT: Thank you very much for the 6 chance to talk to you. Our handouts are actually 7 stapled on the back of Sally's handouts in the back 8 there so you can see hers on developing evidence-based 9 for human protections, followed by the international 10 handouts. But we're going to just talk; we don't have 11 a big PowerPoint presentation for you. 12 INTERNATIONAL RESEARCH 13 Clearly international research is growing 14 rapidly. And this trend suggests the need to keep 15 pace by working to ensure sound policies and 16 procedures to promote protection of both domestic and 17 international research subjects. In the Human 18 Subjects Research Subcommittee, when this issue 19 surfaced and we began our discussions, we had in the 20 entire group discussions about what we thought the 21 issues were. 22 And I can bring these to you by taking you 88 1 through a hypothetical researcher and some of the 2 choice points that that researcher is making as he or 3 she is deciding about how to conduct in an ethical way 4 research that's going to take place in another 5 country. So they're going to begin with local IRB. 6 And the question there will be: does that IRB in fact 7 have the expertise to figure out if this research is 8 appropriate and is going to be conducted in ways that 9 are appropriate culture and country? 10 Then the next question might be: should 11 that research be reviewed by an in-country IRB? Does 12 that IRB there have a Federal-wide assurance? Does 13 that IRB really follow the Common Rule in a way that's 14 equivalent to the way it's followed here? Are there 15 other in-country clearances that might be required? 16 Is that local IRB in the other country really going to 17 provide the kind of oversight that we would expect 18 from an IRB here? 19 Having passed both IRBs, the next issue is 20 in terms of recruitment. Is there in fact the 21 possibility of coercion? The $25 that's paid here to 22 recruit a participant, is that coercive in the context 89 1 of another impoverished country? Or is the access to 2 healthcare that might come as participant in one of 3 these research studies coercive? 4 What about documented informed consent? 5 How is this best documented? What about the 6 translations? What if there are adverse events? Who 7 are these reported to? What about the need for 8 follow-up healthcare after the researchers left the 9 country and the research project is done? What about 10 accusations and complaints that might come up along 11 the way? What about accusations and complaints that 12 reach the press? What about accusations and 13 complaints that reach the State Department? 14 So these are some of the worries that we 15 had going into our discussion. What we did is formed 16 an International Working Group of the Human Subjects 17 Research Subcommittee, and that working group worked 18 to ensure that there are going to be adequate 19 protections of subjects in international research. 20 And this would be by all of the agencies 21 who are subscribers to the common rule, whether we're 22 conducting the research, the Federal agency is 90 1 conducting the research, supporting the research with 2 funds, supporting the research in other ways, 3 regulating the research and involved in other ways. 4 To do this, we invited presentations by 13 different 5 agencies, and we're creating a table that lays out 6 their answers to questions about what is the purpose 7 of their organization; what is their usual involvement 8 in human subjects research?; how do they have 9 oversight of that research?; what kinds of issues 10 might be on the front burner in their particular 11 agency? So agency by agency we're finding out what's 12 going on. 13 At the same time, OHRP is creating a 14 document, International Compilation of Human Subjects 15 Research Protections that goes country by country. 16 And that document lays out from a country by country 17 perspective what are the protections. 18 This is where we are now. In the course 19 of having these conversations, we've looked back at 20 the report to SACHRP in March '04, and that's included 21 in your materials there, to see what were the issues 22 that were coming forward from you efforts to think 91 1 about international issues. 2 And there are three main pieces of what 3 came up in that '04 report. One was infrastructure. 4 The need for training and good IRBs around the world. 5 And the training would be training of the overseas 6 IRBs and training of U.S. PIs who are going to be 7 involved in international research. And we think some 8 significant progress has been made in that in terms of 9 the increase in the FWAs that are around the world. 10 So I was in Shanghai recently, and they 11 said they have about 175 in China FWAs. I didn't 12 check that number with you folks, but that's what they 13 told me. 14 The second issue out of the other report, 15 the '04 report, was the need to systematically review 16 what's going on. And we think we're doing a pretty 17 good job of addressing that in our addressing agency 18 by agency and OHRP addressing country by country. So 19 the systematic review is getting some good attention. 20 The third issue in the March '04 is the 21 issue of regulatory equivalence. And that one hasn't 22 received the kind of attention that the other two 92 1 issues have received. I'm going to let Joan Porter 2 talk to you about the issues that have emerged as 3 we've had our agency by agency discussion. 4 MS. PORTER: Actually, I'd like to start 5 out acknowledging some of the members of our 6 International Working Group who are present here. 7 Many of them are the federal liaisons to SACHRP, and 8 that includes Deborah Holtzman, Roger Cortesi, Lynn 9 Cates, Patty Decot and others in DoD, David Lepay, and 10 I certainly want to acknowledge Ed Bartlett, Dr. Ed 11 Bartlett from OHRP who has done a lot to help this 12 International Working Group move along schedule, 13 presentations, developed some of the charts and table 14 that we are assembling to try to have a good feel for 15 what is going on internationally amongst the federal 16 departments and agencies. 17 As Peg said, the original committee that 18 reported did a really good job on working on 19 infrastructure issues in international settings, but 20 they acknowledge that they left other areas 21 unaddressed to their satisfaction including at least 22 equivalent education for principal investigators 93 1 conducting research abroad, federal harmonization of 2 international standards. And these, we found, in 3 fact, were concerns of all of the federal departments 4 and agencies that presented materials before the 5 International Working Group. 6 We divided our issues that we heard into 7 three categories, roughly. One was regulatory issues; 8 one was ethical issues; and another was 9 communications. And certainly these categories are 10 not discreet in assembling all of the concerns that we 11 heard. And certainly they're not confined to 12 international settings. Some of these issues 13 certainly appear in domestic, particularly multi-site 14 research. 15 So what is unique to international 16 research -- that's what we really wanted to dwell on, 17 but it's hard to do that. It's across the board, 18 across the world. Under regulatory issues, we said: 19 what are the appropriate procedures, policies and 20 guidance for federally conducted, supported or 21 regulated research? What is desirable in terms of 22 consistency? Is more harmonization needed? And how 94 1 can these policies and procedures that we seem to be 2 all creating in our federal departments and agencies 3 separately really making a difference to the ethical 4 conduct of research abroad? 5 Again, a primary, a core concern of the 6 folks who presented to us is, what constitutes 7 equivalent protections as defined in the Common Rule 8 at Section 101(h)? And who determines this, and how? 9 Our understanding is that only federal department and 10 agency that has presented, whose representative has 11 presented to us so far have indicated that 101(h) has 12 been systematically implemented. There isn't really 13 a good understanding of what is an equivalent 14 protection to the Common Rule protections. 15 What clearances are needed in 16 international research? What clearances are 17 appropriate within the federal departments and 18 agencies by the Department of State? And what in- 19 country clearances might be necessary to conduct 20 research appropriately and ethically in international 21 settings? 22 The FWA: currently, of course, the 95 1 Department of Health and Human Services uses the FWA 2 international assurance, and some of the components of 3 the Department of Defense use it, but otherwise there 4 isn't much use of an international assurance mechanism 5 by the other federal departments and agencies. 6 Are these international assurances clear? 7 Are they working? Are they actually used? Do the 8 facilities that have them internationally understand 9 their purpose? Do we need them across the board? Are 10 there sufficient mechanisms in place for oversight and 11 monitoring of research in international settings? 12 And certainly, we always seem to come back 13 to HIPAA. And how does HIPAA apply in other 14 countries? How do we reconcile some of the 15 differences in the privacy and confidentiality laws 16 and expectations? 17 Ethical issues: these are kind of the 18 30,000 foot issues, but we've heard a lot of concern 19 about how do we really affect through our policies and 20 procedures the principles to which we all adhere in 21 our thinking -- autonomy, beneficence and justice. 22 What is owed to individuals in countries by the United 96 1 States federal sector when it undertakes research 2 collaborations? How do policies and deliberations 3 support justice in international settings? Should 4 there be minimum requirements for compensation to 5 subjects if they're injured in international research 6 that is conducted by entities within the United 7 States? And in countries that have few resources, is 8 there the possibility of coercion and undue 9 inducement? And then, what kinds of community 10 involvement are expected in the international 11 settings? And how should this be incorporated into 12 the international research protocols? 13 And lastly, everything that seemed to be 14 flying around like the chart that we saw earlier is 15 communications. Good communications underlies the 16 success of everything. And in some cases, we've 17 identified some areas where there appear to be real 18 gaps. 19 Under communications, we listed: how 20 should United States federal entities communication 21 with international bodies to ensure protections? How 22 do U.S. and local IRBs communicate about a project? 97 1 And what are the roles of the principal investigators, 2 the IRBs themselves, the institutions, the federal 3 sector, in promoting these communications? Where are 4 those gaps? And what are the consequences of those 5 gaps? How can the U.S. federal authorities and IRBs 6 assure that research is done with knowledge of the 7 local context? 8 Of course, as you know, OHRP has 9 emphasized this as a driving consideration in the 10 conduct of international research; but how do we 11 really do that? Can training regarding human subjects 12 protections abroad best be carried out in the United 13 States and international settings? How do we do that? 14 That was one of the emphases of the 15 previous panel of SACHRP. What is the role of the 16 Department of State? What is it doing, or what could 17 it do to foster communications that will lead to 18 better protections? 19 We had a fascinating presentation by the 20 Department of State. They are working now quite 21 closely with the National Institutes of Health, the 22 Fogarty International Center, and probably in the near 98 1 future with CDC and some of the other components of 2 HHS. 3 But with regard to their interaction with 4 the other federal departments and agencies, in terms 5 of learning about what international research is going 6 on and helping inform our embassies about that, there 7 isn't much presence currently. Should there be? What 8 are the political ramifications if something goes 9 wrong in international research? Who talks to whom? 10 How do we get it straightened out? 11 For us in the Department of Veterans 12 Affairs, this has been a little up close and personal 13 lately. We've had some wake up calls about some of 14 our international research that have caused us to say, 15 "We need to be doing things better. We need to have 16 more information about what's going on." 17 And then last, are harmonization of 18 policies and procedures among federal departments and 19 agencies warranted? Do we really need to do this? If 20 we have 13 federal departments and agencies all 21 interacting with different institutions, with 22 different countries, and they're getting different 99 1 messages, is that okay? Is that problematic? Does 2 that detract from how the message we're sending and 3 the job we're doing to protect subjects in 4 international settings? 5 So our hope is that we might work in 6 conjunction with SACHRP. There's a lot we have done; 7 there's a lot we still can do in the International 8 Working Group and the Human Subjects Research 9 Subcommittee. But we would like to see SACHRP 10 consider some of these issues and have some of these 11 areas examined closely with full body deliberations 12 and high visibility. So we're hoping that SACHRP will 13 continue to work on some of the issues presented 14 earlier and undertake some of these considerations in 15 its future activities. 16 DR. PRENTICE: Our next presenter is Dr. 17 Lynn Cates who will talk to us about Multi-Center 18 Studies. Lynn, as you probably know, is the assistant 19 chief research and development officer for the Office 20 of Research and Development at the Department of 21 Veterans Affairs. 22 MULTI-CENTER STUDIES 100 1 MS. CATES: Thank you, Ernie. I've kept 2 track, and at each and every SACHRP meeting that I've 3 attended, which I think is all of them, someone has 4 noted that human research is very different now from 5 the way it used to be, and one of the biggest 6 differences is the fact that multi-center trials are 7 getting bigger and more prominent in human research. 8 Clearly the world of human research has 9 changed, and the ex officios would like for SACHRP to 10 consider looking at alternatives for reviewing multi- 11 site studies as one of its priorities for the future. 12 The purpose of looking closely at 13 alternatives for reviewing multi-site studies is to 14 promote the highest quality review while enhancing 15 efficiency. Is it possible -- we'd like to see if 16 it's possible to figure out how to ensure that there's 17 appropriate ethical and scientific review, and very 18 difficult to look at sensitivities to community 19 attitudes. 20 How can those things be maintained while 21 efficiency is enhanced? Is there attention there that 22 can be addressed? We think that there actually is a 101 1 potential to improve quality by using alternative 2 mechanisms, but we need for SACHRP to help us look at 3 that. 4 Currently, there are several alternatives 5 for review of multi-site studies, and these can be 6 roughly lumped into four categories. The first is 7 multiple local IRB review of studies. For instance, 8 at the VA, we have many large multi-site studies, and 9 if a study currently involves 77 different sites, it 10 has to be reviewed by 77 different IRBs. 11 This process can take upwards of a year 12 and a half to two years, and by then the science can 13 be outdated as well as funding cycles messed up, et 14 cetera. You can imagine all the logistical 15 nightmares, as well as the costs entailed in having 16 personnel dedicated to just tracking down 77 different 17 IRBs, not to mention all of the suggestions they make 18 for changes in the consent form. So this is one 19 model, and this is what is being done most of the time 20 nowadays. 21 A second is independent IRB review. 22 Examples of this are Chesapeake, Quorum, Western and 102 1 other independent IRBs. And in this model the 2 multiple sites in a multi-site study all agree to 3 accept the review of an independent IRB. A third 4 model is facilitated central IRB review. And in this 5 model, a good example is the NCI central IRBs, the 6 pediatric and the NCI -- well, the NCICRB and the 7 pediatric central IRB at NIH. 8 And in these models, a local IRB can defer 9 to the central IRB. They can suggest modifications or 10 they can do a full review on their own. And the last 11 model is IRB reciprocity. An example of that is MACRO 12 where five academic institutions got together and 13 agreed that one of them could serve as the primary IRB 14 for collaborative studies. 15 Clearly, although there are several 16 different models, the one that has been talked about 17 the most over the years are central IRBs. And as 18 you're all aware, there are many pros and cons for 19 central IRBs, and I'll just review a few of them. 20 One of the most important potential 21 advantages is consistent expert ethical and scientific 22 review. In many cases, and we see this at the VA 103 1 where there are relatively small institutions that 2 have their own IRBs and in some cases, the only expert 3 who is available is the investigator his or herself, 4 and that person is conflicted; can't serve on the IRB 5 and provide the expertise. And so good -- there's a 6 much larger pool of experts that can be drawn upon 7 with central IRBs. 8 Certainly, you could provide more training 9 and experience for IRBs in certain kinds of protocol 10 reviews. And an example here is that some independent 11 IRBs review dozens, if not hundreds, of industry- 12 sponsored studies whereas a local hospital IRB might 13 review only a couple or a handful a year at best, and 14 may not be as familiar with the ins and outs of 15 industry-funded studies. 16 Another potential advantage is centralized 17 accountability so that each site doesn't veer off a 18 little bit differently in handling the protocol. One 19 of the things that was mentioned yesterday as a 20 potential advantage for central IRBs is the potential 21 for earlier identification of trends in adverse events 22 and other kinds of problems as the study progresses. 104 1 In my mind, a very important advantage of 2 central IRBs could be the elimination of local 3 institutional conflict of interest. And by this I 4 mean I think all of you have heard of instances where 5 pressure has been put on IRBs from institutional 6 officials because the IRB approval is the only thing 7 standing between the institution and hundreds of 8 thousands, if not millions, of dollars in grant 9 funding. 10 And this has particularly been a problem 11 with just in time reviews when all the i's are dotted 12 and t's are crossed, and the only thing left is IRB 13 approval standing in the way of getting that grant 14 funded and started. 15 Certainly central IRBs could reduce local 16 administrative burden and provide a more efficient 17 review process. We're talking here in terms of 18 reviews that would -- and approvals that would take 19 only a matter of weeks rather than a matter of many 20 months to the couple of years that I cited earlier. 21 And last but not least, another potential 22 advantage is improved access to multi-site studies by 105 1 subjects and individual investigators. This is 2 particularly true of small facilities or private 3 clinical offices that don't have the infrastructure or 4 the resources to support an IRB of their own. 5 Just like there are many advantages, there 6 are many challenges for central IRBs as well. One of 7 the most important is local accountability. Who is 8 actually responsible for human research at the local 9 level? And that's going to be a very thorny issue 10 that must be sorted out. 11 A second very important issue is going to 12 be sensitivity to community attitudes. And I think 13 very importantly at a SACHRP meeting several months 14 ago when there was a panel on central IRBs, the new 15 paradigm was proposed, and that talked about a little 16 bit earlier today as well, that patient advocates, 17 disease specific advocates might be representatives 18 than people from a local geographic community. And 19 this needs to be explored. 20 Liability comes up early and often as a 21 challenge. Conflict of interest. Even though you've 22 removed local institutional conflict of interest, 106 1 there may be other kinds of conflict of interest. For 2 example, if NIH has a central IRB or the VA has a 3 central IRB and is funding the studies, could there be 4 a perception of conflict of interest? If not, real 5 conflict of interest, of course. 6 Another challenge is that some local IRBs 7 may go out of business. And in the VA we think that 8 this is likely to happen, that some of the smaller 9 ones will. But they don't really have critical mass 10 anyway, and they've found it a big struggle to have 11 the resources to maintain an IRB. 12 A very important challenge is going to be 13 ownership by local IRB chairs and members. People who 14 have been chairs and who have been invested in IRBs 15 for a long time often think that -- or may think that 16 they do IRB reviews the very best. And will they 17 trust a central IRB to perform the reviews? And so 18 this will need to be addressed. 19 And another challenge is to eliminate 20 duplicative reviews. It doesn't make sense to have 21 central IRB review and then have a full local IRB 22 review that drags down the process; it makes it even 107 1 longer than it was to begin with. 2 These pros and cons you've heard over and 3 over again along with several others. These were just 4 some of the tip of the iceberg. But the bottom line 5 is not much progress has been made in setting up 6 alternatives for multi-site review. This just has not 7 really caught on. 8 And so an IRB invitational workshop has 9 been planned to not just go over the pros and cons of 10 central IRBs or other alternatives, but to try to 11 develop concrete models for how you can look at 12 reviewing studies, particularly multi-site studies. 13 This workshop will be held November 17th 14 and 18th here in Washington. And the steering group 15 includes Bern Schwetz; Amy Patterson and Allan Shipp 16 from NIH; Susan Ehringhaus who is a very fine attorney 17 at the AAMC; Lowell Schnipper, who spoke before SACHRP 18 a few months ago about central IRBs, he's from the 19 American Society for Clinical Oncology; and me from 20 the VA because we are planning a central IRB for the 21 VA right now. 22 The workshop is invitational, and the 108 1 reason it's invitational and small is so that we can 2 actually get work done; so that we can actually create 3 models that we can propose to SACHRP. This is an 4 exploratory meeting, and what we plan to do is create 5 straw men for others to address in future dates. 6 The workshop will include attendees from 7 diverse backgrounds that will include a lot of IRB 8 experience, academic and community based 9 investigators, attorneys, subjects, ethicists, 10 industry officials, and senior university and medical 11 school administrators. The charge of the workshop was 12 laying out on the table in the back. I think we've 13 run out of copies, but if anybody needs a copy of the 14 charge for the workshop please let me know; we'll be 15 happy to get you a copy. 16 But the topics that will be looked at will 17 be institutional responsibilities and concerns, 18 including liability; ways to reduce burdens, 19 especially for the multi-site trials, although we will 20 think about single site trials particularly 21 international trials as has just been talked about. 22 We will look at barriers to adopting 109 1 alternative models if IRB review such as cost and 2 again, liability. And we'll also have representatives 3 OHRP and FDA present so that we can look at the 4 federal policy framework that's relevant to these IRB 5 arrangements that we propose to make sure that either 6 we're working within the current federal regulatory 7 environment, or if there are things that need to be 8 changed we can start thinking concretely about changes 9 that might need to be made. 10 The follow-on activities of the workshop 11 will be twofold. The first will be a report that will 12 come to you at SACHRP, and this report will be on the 13 suitability of alternative models for review of 14 different particular research contexts. Again, these 15 will be concrete models. And the second will be 16 strategies to address the barriers to the use of these 17 alternative models. 18 And the other follow-on activity will be 19 that there will be a public meeting so that everyone 20 who is a stakeholder or who is interested in 21 alternative models will be able to participate, talk 22 about these straw men models, and help us discuss and 110 1 refine them. Thank you. 2 DR. PRENTICE: Thank you Lynn. And our 3 next presenter is Dr. Sally Flanzer, who is the Health 4 Scientist Administrator, Division of Policy, 5 Coordination and Analysis, Office of Extramural 6 Research, Education and Priority Regulations, Agency 7 for Healthcare and Quality. I hope I got that right. 8 Thank you Sally for agreeing to address 9 SACHRP. And she will be talking about evidence-based 10 practice. 11 EVIDENCE-BASED PRACTICE 12 DR. FLANZER: First, I'd like to thank the 13 committee for providing us, the ex officios, with the 14 opportunity to discuss -- to participate in your 15 discussion about what to do next. And I would like to 16 suggest that SACHRP select developing an evidence- 17 based for human protections as a future topic. 18 I'd like to begin by thanking Jeff Rodamar 19 from the Department of Education for his help. I take 20 full responsibility for what I'm about to say, but 21 Jeff provided me with considerable assistance on the 22 substantive content. And Jeff and Ivor Pritchard who 111 1 is now at OHRP, were the significant contributors to 2 a report that was produced by the social and 3 behavioral working group, the SHRS committee, on 4 evidence-based -- on the need for an evidence-based. 5 Right now, we operate primarily in an 6 expert-based system, and SACHRP and the subcommittees 7 and OHRP and each of the human protections 8 administrators in each of the agencies, we're really 9 smart people. We've got a lot of anecdotes and we've 10 got past experience and we have assumptions, but we're 11 comfortable giving advice, but we're pretty short on 12 organized evidence. 13 In the materials you'll have two slides. 14 One is used at my agency, at AHRQ, and that's the one 15 that's up now. With thanks to Dr. Kenny Fink from the 16 practice-based research network. And the second slide 17 was presented at the NIH clinical center bioethics 18 training program, Dr. Robert Trug from the Harvard 19 Medical School. 20 What both of the slides have in common is 21 that they talk about levels of evidence and the nature 22 of a cumulative evidence building routine to learn how 112 1 or know something. If you go back to the slide from 2 AHRQ, the pyramid represents the kind of evidence 3 that's needed before the practiced-based research 4 networks feel confident about translating research 5 into practice guidelines. 6 So I'm taking this model to apply that to 7 some recent innovations in human protections programs. 8 Many of the questions about human protection program 9 operations would profit considerably from an 10 accumulated building evidence approach. The 11 discussion about centralized IRBs would profit from 12 evidence about decisional consistency and decisional 13 processing. 14 We could ask what's been the impact of 15 accreditation on participant protections, or on 16 adverse events. Will clinical trial registries affect 17 the public's perceptions and feelings about honesty 18 and science? We're not short of questions, but we 19 are, I think, very short on mechanisms and pressure to 20 get those questions asked and answered. And this is 21 where I think SACHRP can be a very powerful player. 22 I think SACHRP can do four very useful and 113 1 important things. You can make preliminary 2 suggestions about the shape of a coordinated research 3 activity. You can prioritize the content of a 4 research program. You can make suggestions about how 5 to fund the activity. And then you could be very bold 6 and make a recommendation about a federal home for 7 this research activity. 8 So let's start at the beginning, about the 9 shape of a research program. Like a good researcher, 10 everything begins with a systematic review and 11 analysis of the literature and a preliminary analysis 12 of existing data. Even if we restricted the data 13 analysis to just federally funded research, we could 14 look at the bioethics research at the NIH clinical 15 center, at the Fogarty and Bioethics Fellows Programs, 16 at the Office of Research Integrity Grant Program, at 17 NSF. There is some research being done. So even just 18 this kind of agency sponsored inventory on effective 19 protections would be a very valuable first step. We 20 could take the low-hanging fruit, in other words. 21 We're almost ready to collect date about 22 adverse events. There is some out there. We've got 114 1 a database on ORI infractions. There is information 2 about OHRP investigations. So what if we just started 3 by triangulating those three data sources? It's a 4 place to start. So if we had an inventory and some 5 preliminary analysis, we could at least begin to see 6 the spokes and the hubs of our area, and we could see 7 these gaps much more clearly. 8 So we'd begin to see some shape, and then 9 SACHRP could, knowing that shape, could discuss and 10 prioritize the most pressing questions inside that 11 organizing frame after we identified -- or after you 12 identified the knowledge goals. So what might be the 13 content of a research program? 14 Well, in no particular order, we would 15 certainly be assisted by having empirical knowledge of 16 process and of risk and of risk assessment and 17 protections. We could benefit from outcomes research 18 or effectiveness research or identification of best 19 practices. All of those goals are possible. SACHRP 20 could choose one. 21 Simply descriptive counts would be 22 beneficial in many cases. Can we establish 115 1 performance or quality indicators? Should we look at 2 the business impact, at the business case? For 3 example, requiring literacy or numeracy or 4 comprehension assessments prior to obtaining informed 5 consent? Studies on all of these would improve IRB 6 operations, as well as protections. 7 Right now, I think there's interest on the 8 part of many disciplines from sociology and social 9 work, ethicists, health services, researchers, 10 organizational development people, systems engineers, 11 lawyers, psychologists. I think these interests would 12 coalesce very profitably if money existed, if there 13 were a funding stream. It's the "If you build it, 14 they will come" model of trying to build information. 15 The Office of Research Integrity gets a 16 very respectable interdisciplinary response to their 17 request for applications on research integrity. Jeff 18 Rodamar found more than 100 studies on IRB operations, 19 most of them bio-medical and most being published 20 since 1999, in response, we think, to crises and 21 shutdowns. So we have some interest, and SACHRP can 22 help meet that interest. 116 1 So what I'd like to do next is do a quick 2 review of what are the federal management program 3 options. Federally sponsored research efforts can be 4 done incrementally or as large big events. We can 5 have a huge kickoff investment of dollars, or we don't 6 need a big budget initially. The program can be small 7 and incremental, but every program needs a home. And 8 I'm going to leave the home question for last. 9 So I'm going to suggest three vehicles 10 that can start a federal research program on human 11 protections programs. And yes, I'm going to ask you 12 to dispend reality and pretend that we can get budget 13 for this because that's going to be essential. 14 Globally, the three options are a report, 15 a contract or a grant program. That's pretty much 16 what's available to us as Feds. OHRP could commission 17 a very specific NRC report to identify a research 18 agenda. They would look at the existing evidence base 19 and lay out the agenda. They'd define terms, identify 20 problems, define the scope, look at existing 21 methodologies and instrumentation and set priorities 22 for developing the evidence base that could improve 117 1 both operations and outcomes in human protection 2 programs and the human research enterprise. 3 In essence, what we -- what the report 4 could ask for was to develop a science policy for 5 human protections research. The study director would 6 have the job of seeking out small contributions of 7 funds from interested audiences of federal agencies. 8 And anybody that's doing human protection -- that's 9 doing research with human subjects should be convinced 10 to make a small contribution. 11 No doubt there are many of you on SACHRP 12 who would be invited to be on the expert panel. Now, 13 why might this be a good thing to do now? Well, 14 there's lot of support, previous reports, that suggest 15 that there is a need for an evidence base. So we 16 don't have to demonstrate need, but very short budgets 17 -- small budgets in agencies might mean that there are 18 small pots of money available in many places that can 19 be put together profitably. No one place is going to 20 have enough budget to do this all. 21 The strength of the activity of a report 22 is that it actually lays out future activities. The 118 1 weakness is that it may not create ownership. You can 2 gather a lot of information, but when the report is 3 done, it's done. And there are probably many of us in 4 this room who have been involved in reports and a 5 change of administrations and the report now is on a 6 library shelf somewhere. 7 The second vehicle is to write a contract, 8 and I think OHRP can write contracts and issue 9 contracts. They still might need interagency 10 agreements to get budgets together, but we could get 11 a contract with a Beltway bandit or an academic 12 program to gather data. 13 Let's pretend for a minute that SACHRP 14 recommends a contract to collect data about IRB and 15 human research protection program processes from every 16 Extramural grant funded by NIH. Just for fun, let's 17 pretend, okay. A contractor would go through OMB for 18 a data collection approval and data would be collected 19 as a reporting requirement of the terms and conditions 20 of the approval of the grant. It could be information 21 that actually exists already -- IRB dates, when 22 submitted, when approved, expedited, full review, 119 1 number of iterations, number of changes, data safety 2 planning, research training in human protections, 3 adverse events. The contractor handles the OMB 4 submission. They could create an electronic form for 5 data collection, annual collection, issue an annual 6 report and final reports identifying barriers to 7 protection. 8 Actually, there is a window of opportunity 9 for something like this now. As HHS switches to the 10 uniform use of the electronic 424 submission form from 11 the PHS398 form, this is going to upset the apple cart 12 in all the academic institutions, in many of the 13 academic institutions. So the data collection could 14 be justified in part by an acknowledged lack of 15 evidence, and by shameless reference to past 16 disasters. And to use this moment of calm to gather 17 evidence, to avoid shutdowns and disasters. And now 18 would be the time to begin this systematic 19 investigation. 20 And I think also unfortunately the failure 21 of one of the two independent accrediting agencies can 22 raise -- we can use that to raise questions about the 120 1 enterprise's ability to self regulate, and you know, 2 be shameless. If we're going to ask, ask big. 3 The strength of a contract is that it's 4 controlled. It's very controllable. It gathers a 5 high volume of highly credible information, but it 6 doesn't impact the federal infrastructure. So we 7 could be all done and have our reports and still not 8 have anybody own the concept of supporting an 9 evidence-based program approach. But we sure would 10 know a lot more than we know right now. 11 So the last vehicle I'd like you to 12 imagine is that somebody runs a grant program, an 13 Extramural competitive grant program. SACHRP could, 14 if they wanted, identify an agency and say, "This is 15 where this program should sit. This is who should be 16 there." 17 And SACHRP could offer that mandate and 18 make suggestions for seed money, and then there would 19 be a RFA. Well, no, not an RFA anymore -- an FOA, a 20 funding opportunity announcement. And four years from 21 now, we'd have a program that actually was collecting 22 information, and building an infrastructure of young 121 1 researchers who were being led to this topic by the 2 availability of funds. The money seduces people into 3 areas. 4 So we could apply science to the process 5 of doing science. We could set very high standards 6 for peer review and provide clear research questions 7 and outcomes of interest. We could have a kickoff 8 conference and annual meetings. We could publish and 9 disseminate. And wouldn't it be lovely if that 10 happened. 11 The strengths of an Extramural grant 12 program is primarily in developing a cadre of 13 researchers who are committed to this topic, as well 14 as accumulating the information from the grant 15 programs. You really need a lot of money to do it 16 right, enough money to make a real contribution and to 17 generate a critical mass of knowledge. The downside 18 is that it's going to be a difficult environment to 19 start up a new program like this now. But if I were 20 going to run a program like this, I'd want $3 million 21 a year for five years. 22 Now, that's not a lot of money by 122 1 submarine standards, but it's a lot of money in social 2 science or science policy shops. There are other 3 vehicles. You can hold planning and consensus 4 conferences. You can do all of those things in 5 addition to these three vehicles, but all of them need 6 to help develop a direction and alert the field to the 7 government's intentions and get buy-in from those who 8 have the expertise, and who just might be threatened 9 by an evidence-based approach to what is an expert 10 turf issue right now. 11 So regardless of the vehicle that SACHRP 12 suggests, I do encourage the committee to think about 13 this issue again and push for a broader, deeper, and 14 less partitioned view of human subjects protections 15 for the research enterprise. Investigator behavior, 16 institutional processes, and the protection of human 17 subjects have to be knit together somewhere. 18 So in Fed world, somewhere is the 19 question. Every program needs a home. Who's going to 20 do this? Well, I'm really going to leave that up to 21 you. I have an opinion, but it's just an opinion. 22 The problem or the challenge of finding a federal home 123 1 is that that's your access to the rest of the pipeline 2 in both directions -- to funding, to commitment, and 3 to the people who are going to be doing the research 4 on the other side. 5 So you need to find a home, I would say to 6 SACHRP, find the topic a home; recommend a vehicle; 7 identify the most pressing questions; and frame the 8 inquiry. And I would suggest that that's what you do 9 next. 10 DR. PRENTICE: Thank you Sally. The next 11 presenter is Dr. Deborah Holtzman, who is the director 12 of the Office of Scientific Regulatory Services, 13 Office of the Chief Science Officer, Center for 14 Disease Control and Prevention. Although I've got 15 another title here that says Acting Deputy Associate 16 Director. So I'm not quite sure which is accurate. 17 But at any rate, welcome Deborah. Thank 18 you for agreeing to address us. And I'm looking at 19 your PowerPoint which has a broad title, Regulatory 20 Burden in Public Health Practice, but I know that 21 you're going to be focusing perhaps a little bit on 22 exemptions. Is that no correct? 124 1 DR. HOLTZMAN: That's correct. 2 DR. PRENTICE: Okay. 3 DR. HOLTZMAN: Thank you Dr. Prentice. 4 DR. PRENTICE: Thank you. 5 EXEMPTIONS 6 DR. HOLTZMAN: And I'm doing both jobs 7 right now, but hopefully we're going to fill one of 8 those positions and I'll only have to do one job which 9 will be the director of the Office of Scientific 10 Regulatory Services. 11 Okay. As Dr. Prentice said, I'm going to 12 talk about exemptions, but I titled this Regulatory 13 Burden in Public Health Practice, and you'll see why 14 as I continue. Okay. As you're well aware, Section 15 102 of the Common Rules defines research that is 16 subject to the regulation, and specifically research 17 involving humans. Section 101(b) specifies the type 18 of research that is exempt from regulation. And then 19 of course, beyond Common Rule, Subparts B, C and D. 20 Our specific focus, and here I'm talking 21 on behalf of CDC, is on category 5 which is research 22 and demonstration projects which are designed to 125 1 study, evaluate or otherwise examine public benefit or 2 service programs. 3 As stated in some undated OPRR guidance, 4 the following benefit or service programs are exempt: 5 those that deliver a public benefit or service, 6 however, this is not clearly defined in the 7 regulation; those that are conducted pursuant to 8 specific federal statutory authority, although it is 9 unclear how specific; those where there is no 10 statutory requirement for IRB review; and those that 11 do not involve significant physical invasions or 12 intrusions upon privacy. However, it's not exactly 13 clear what this means in the regulation. 14 So this is the proposal that we would like 15 to present for SACHRP's consideration: To examine and 16 recommend an expanded interpretation of Category 5 to 17 include a broader range of public health activities, 18 also known as public health practice which is often 19 distinguished from public health research. 20 And in this process, we'd like to include 21 public health stakeholders in this process of 22 examination by such agencies as the Council of State 126 1 and Territorial Epidemiologists or the Association of 2 State and Territorial Health Officers, or the American 3 Public Health Association. 4 So why such a proposal? Essentially to 5 enable CDC to best carry out its mission, which is to 6 protect the public's health. And I want to quote 7 here. There was a recent article by James Hodge that 8 was published this year in the Journal of Law, 9 Medicine and Ethics. And he said, "Misclassification 10 of public health practice activities as research can 11 result in these activities being delayed or conducted 12 less efficiently or at higher costs due to the need to 13 adhere to the regulations." 14 This does not mean that ethical issues 15 will not be considered in public health activities or 16 public health practice. So what -- for example, what 17 we would like to propose and for SACHRP to consider is 18 expand the interpretation of Category 5 to include 19 selected public health activities such as prospective 20 collection of biological specimens for authorized 21 surveillance purposes, which is currently not exempt; 22 data collection for government accountability in 127 1 service programs, and this would cover a lot of our 2 activities that are sort of under the category of 3 program evaluation; and then expansion of the federal 4 role to state, local, tribal and foreign governments 5 beyond, for example, allowing a waiver of informed 6 consent at Section 116(c). 7 For example, the OPRR guidance on Category 8 5 limits the scope to the federal statute and Section 9 116(c) contemplates IRB review of some state-level 10 public service programs. And we would recommend that 11 they would be able to use this exemption as if they 12 were just like the federal level. 13 Okay. And just a couple of other 14 considerations. Should child exception to Category 2 15 be less restrictive -- for example, when the child is 16 a third party subject -- allowing the collection of 17 identifiable, private information on children from 18 parents seems consistent with that intent, but this is 19 currently not exempt. And then, should prisoner 20 research be exempt under Category 4? 21 Use of anonymized existing data or 22 specimens from prisoners imposes no greater risks or 128 1 potential benefits than among non-incarcerated 2 persons. And again, this activity is not currently 3 exempt. And then lastly: can research with prisoners 4 be exempt under Category 2 when they are third party 5 subjects? In other words, when there's no 6 investigator interaction. 7 So that's our proposal. Thank you. 8 DISCUSSION 9 DR. PRENTICE: Thank you Deborah. Would 10 all the panelists assemble up at the front table, 11 please? 12 All right. This is what I propose: We, 13 according to the schedule, have got 48 minutes before 14 lunch. We have four areas; that's 12 minutes apiece. 15 If I add that up, that comes out to 48 minutes. What 16 I propose is this: we will confine questions for 12 17 minutes to each subject sequentially. That way we're 18 not all over the waterfront. 19 Starting with international research. And 20 then we're going to go to lunch and we're going to 21 come back. And then after lunch, we have really two 22 and a half hours to engage in further discussion. 129 1 Okay. So we will continue the discussion after lunch. 2 Does that sound like a reasonable plan? So let's 3 start with international research. And I get the 4 first question. 5 And I'll only ask one question. How's 6 that? We all know that more and more in particular 7 clinical research is migrating overseas, going to 8 developed countries and developing countries. And of 9 course, we're aware of the fact in some cases that 10 research is funded by the federal government and there 11 are FWAs in place; and in some cases, it's not funded 12 by the federal government, but it might be -- the data 13 might be imported into the U.S. to support an NDA. 14 So considering the fact that we have 31 15 years since the National Commission was formed in 16 response to all of the exposes on ethical research, 17 and over the years we've been working pretty hard with 18 a few bumps along the road to evolve our HRPP system 19 to where it is today. And now all of a sudden, we've 20 got this tremendous migration of research overseas, 21 and despite the fact that there are guidelines in 22 place -- there's the Declaration of Helsinki and ICH, 130 1 et cetera -- how far do you think they are behind us, 2 if they are behind us, at all? Or do we just not know 3 that information? 4 DR. BARRATT: I think that we don't know 5 is a good part of the answer. The country with the 6 most overseas research is Canada, and that's not a 7 place that we're terribly worried about. They've 8 followed a trajectory that's not unlike ours in terms 9 of protection of research involving human subjects. 10 But the big growth areas are the countries 11 where the research can be conducted much less 12 expensively, where there may be special populations of 13 interest. And it's worrisome, and I don't think we 14 have a handle on it. 15 DR. PRENTICE: That's what I thought you 16 would say. 17 MS. PORTER: Ernie, may I comment? 18 DR. PRENTICE: Yes. 19 MS. PORTER: I think you hit on an 20 important word, which is "behind." I don't think 21 every place is behind; I think they're just different 22 and we don't know the extent to which they're 131 1 different. And we don't have a good standard of what 2 is acceptable by adopting or recognizing other 3 international codes. So that's one of our first 4 issues, is to harmonize what we think is the de 5 minimus in terms of protection requirements. 6 DR. PRENTICE: I guess my follow-up 7 question to that would be: yes, you do have different 8 international codes and standards that ostensibly the 9 country which subscribes to those codes or standards 10 are supposed to follow. But do we know whether or not 11 they indeed follow those standards? 12 DR. BARRATT: And that's the question, the 13 gap between the policies which are there and the 14 actual practice on a case-by-case basis. And that's 15 where it's worrisome, and I don't think we have data. 16 DR. PRENTICE: Okay. I want to ask one 17 more question, but I don't want you to answer it yet, 18 because I want to have further discussion. I want you 19 to think about it. You indicated that you wanted 20 SACHRP's help and you also said, "Well, they could 21 look at one or more issues." So I want you to think 22 about how we can assist in the resolution of some of 132 1 these issues. 2 And you know how SACHRP works. SACHRP has 3 subcommittees, or we have panels, we have a contract 4 with the IOM, we ended up having -- I don't know if 5 it's called a contract or not, but the thrust of it 6 was that the ASCO and AAMC now have a workshop that 7 they're looking at, at IRB models which arose out of 8 our consideration of that topic by a panel. 9 So I want you to think about what you 10 think we could actually do in this -- what I consider 11 to be an absolutely enormous area. I mean, I can look 12 at Subpart D and I can look at Subpart C and I can 13 say, "You know, it's relatively confined." I can 14 almost figure out a roadmap. But when you're talking 15 about this vast array of international research in 16 hundreds of countries, boy, I don't even know how to 17 approach that. So think about that. Open to the 18 floor. 19 DR. GYI: Just as a point to follow-up on 20 that, Dr. Prentice. And as we're thinking about this 21 from answering the question, I wonder if there's a 22 rule for accreditation to help facilitate that thought 133 1 process to help at least anchor some point -- a 2 starting point so that we can move ahead with this. 3 And perhaps after lunch we can pick up on that. 4 If no one else has any questions, I do 5 have a question about -- we only have 12 minutes, so 6 we got to be efficient. 7 I just came back from India at the request 8 of a summit that was being put on by Professor Falguni 9 Sen from Fordham University and the health 10 administrators and appropriate folks over there 11 looking at capacity building. And as you can imagine, 12 all of these issues were addressed. And issues of 13 investigative certification and accreditation did come 14 up. 15 And I wondered if you had had a chance to 16 think about how we might -- again, I don't know if 17 it's appropriate for us to start this question now or 18 pick it up later on -- but if you had thought about 19 from the international research perspective, how we 20 blend equivalent protections without being realistic 21 on our side of looking at our regulations and 22 enforcing it in a way that is perhaps not even 134 1 feasible for them, whoever them is, to comply with? 2 MS. PORTER: I think there is an attempt 3 through the FWA -- the Federal Wide Assurance -- and 4 the international area to come to a common 5 understanding of what are basic protections by, 6 certainly acknowledging the fact that there other 7 international codes, other international policies that 8 are widely recognized. 9 And then the international assurance 10 actually brings in under the terms of the assurance 11 other aspects of the Common Rule that may not be 12 addressed in the international codes cited by the 13 other institutions in the other countries, but that 14 would fulfill some basic requirements in the common 15 rule. So that's one way to make the process a little 16 smoother, I think, in acknowledging that the U.S. is 17 not the only country that has thought about these 18 issues or that cares about these issues. 19 DR. PRENTICE: Ada Sue. 20 MS. SELWITZ: Again, I apologize if this 21 was brought up while I had to leave momentarily. But 22 this is more of a comment perhaps than a question, but 135 1 it's in response to Dr. Holtzman's recommendations on 2 exemptions. 3 DR. PRENTICE: We're not talking about 4 exemptions. 5 MS. SELWITZ: You're doing it -- I missed 6 that. I apologize. 7 DR. PRENTICE: Later. You have 12 minutes 8 later. Celia. 9 DR. FISHER: I have a question really with 10 respect to what we might be talking about later this 11 afternoon. When I remain -- I think all the issues 12 are really important. It's still unclear to me how 13 federal regulations, both with respect to DHHS and the 14 FDA regulations, actually operate internationally, and 15 how much research is sponsored by DHHS so that it is 16 regulated out there; how much comes under the rubric 17 of FDA; how much does not. 18 And so it's kind of difficult if we want 19 to take a regulatory approach to some of your issues, 20 at least for me at the moment, to figure out where 21 that regulatory approach would lie. 22 DR. BARRATT: We tried to get a handle on 136 1 the general order of magnitude of the investments, and 2 it is hard to get a handle on that. But there's 3 clearly millions and millions and millions of federal 4 dollars that are being spent on research that's 5 conducted overseas, some of it conducted by our own 6 people and some of it through grants and some of it 7 through contracts. 8 So if we're talking about where are our 9 tax dollars going, they are going to these investments 10 in a major way. And that's part of our interest in 11 being sure that it's done well. 12 DR. PRENTICE: Susan. 13 MS. KORNETSKY: One of the things that you 14 brought up was the whole issue of education and 15 training. And I know that there was just announced 16 another round of grants out there for specifically for 17 education training, specifically in international 18 research issues. 19 And when I went on that site to look at 20 that, there was also a whole list of grants that had 21 already been awarded and work that had been ongoing. 22 And sort of thinking of some of the discussion that 137 1 Sally mentioned about sort of evidence-based, I'm 2 wondering where there is stuff that has -- again, not 3 globally in all the areas, but in some of the areas 4 that you've done -- that has already been done that 5 has been sort of looked at to see what has already 6 been done, what's ongoing, what has been successful in 7 some of those educational programs? 8 DR. BARRATT: I'm not sure we know the 9 answer to that one, either. In the case of the United 10 States, we sort of saturated it so that most 11 institutions that could or should have IRBs do. And 12 so we might be doing training in terms of bringing new 13 people through those existing organizations. But 14 that's clearly not the case internationally, so that 15 there's almost an incessant need for the training 16 because of the growth of this international research 17 enterprise. 18 MS. PORTER: We do know that the Centers 19 for Disease Control and Prevention, for example, has 20 a program for training investigators who are doing 21 international studies. And certainly we're aware that 22 many institutions to whom HHS gives grants and other 138 1 federal departments and agencies give grants have 2 policies and procedures, but they're not shared across 3 the board, and they're not all consistent. 4 And as Peg says, it's such a rapidly 5 growing and developing community, there are no 6 specific requirements on the part of the federal 7 sector for international training and awareness per 8 se. 9 MS. KORNETSKY: I think you're right. 10 Some of those programs, I think, were geared towards - 11 - even though they were awards here, training in the 12 other countries as well. And I guess the only thing 13 I'm suggesting is instead of sort of reinventing the 14 wheel, it looks like there has been some federal money 15 spent already looking at some of these initiatives. 16 Instead of sort of starting from scratch, there may be 17 some good ideas out there in hopes of making it a 18 little bit more consistent or ways of approaching it. 19 DR. PRENTICE: James. 20 DR. POWELL: You've talked a lot about 21 federally sponsored research that's going outside the 22 country, but a lot of the drivers come -- for new 139 1 studies going into lower cost countries come from 2 private sponsors. And I wonder if you anticipate that 3 there are going to be different standards based on 4 where the data are going to be used? Meaning if the 5 data are going to be brought back to the U.S. versus 6 data being used in a specific locale. 7 DR. BARRATT: I think you are just raising 8 really solid questions. This is worrisome because the 9 data may be collected through private sector 10 investments and we want to use it in some public 11 regulatory context here. And what is the articulation 12 between the ways that that work is conducted? 13 This private sector investment in research 14 issue also came up when we were talking about what is 15 going to come across the State Department's desk when 16 there are mistakes made or accusations raised? If it 17 is NIH funded research, the State Department actually 18 knows what NIH funded research is taking place in that 19 country. There's no checkpoint to be sure that we 20 know the private sector research or the research from 21 any of the other agencies. So that has tremendous 22 potential for problem. 140 1 MS. PORTER: I think I hear in your 2 question and comment also the idea of justice. If 3 we're going out to collect data from other countries, 4 that it really doesn't have much benefit for the 5 citizenry of those countries, and we bring it back 6 here for the benefit of our own population in the 7 United States. How should we reconcile that activity 8 or comment on that so that we address better the 9 principal of justice? 10 DR. PRENTICE: Okay. We're out of time. 11 You'll have lots of time later, so hold the thought 12 that you have. I want to move now into the 13 alternative models for reviewing multi-site studies. 14 Address your questions to Lynn. And I'll start off 15 with one question. 16 As far as I know, there are only two 17 central IRBs that are funded by the federal 18 government, the NCI adult and pediatric IRBs. But 19 there's lots of institutes out there that fund 20 studies. Is there any talk, any initiatives to have 21 more central IRBs located with NIH? 22 MS. CATES: The VA is definitely going to 141 1 have a central IRB. We're working on that. And I'll 2 ask the NIH representative -- 3 DR. PATTERSON: No. There hasn't been any 4 formal discussion of expanding the NCI model in other 5 institutes, but certainly, I think, there are other 6 institutes that are looking at that model and maybe in 7 the future they would be. But I'm not aware of any 8 specific effort on the part of another institute to 9 adopt it. 10 MS. DECOT: The Department of Defense has 11 one already in existence in the national capital area 12 for cancer research, and our medical hospital system 13 is located in this area. And then we're also starting 14 to look at the process for responsibility, in forming 15 what we're calling a little bit more topical IRBs, so 16 that when we have a topic of personnel surveys, of 17 non-lethal weapons, of intel community employee survey 18 type protocols, to either have a central IRB or an IRB 19 that's identified as an expert in this area. 20 So we're just starting to look at it 21 within our department of how we can work the assurance 22 process, the liability process, the oversight process, 142 1 and how can we do that efficiently. 2 DR. PRENTICE: Okay. Thanks. Ada Sue. 3 MS. SELWITZ: All right. And again, I 4 want to thank all the panelists. I think it enhances 5 the quality of what SACHRP does when we receive 6 feedback from the ex officio members. And I think 7 it's very important. And I liked it at the Subpart A 8 Subcommittee meeting and I think it's excellent, so I 9 commend you all for including this on our agenda. 10 So I have two questions, and one is 11 probably directed to you, and one I guess I'll send 12 back to NIH. And I'll start with NIH. Has there -- 13 and Sally probably got us started thinking about 14 evidence-based issues. But has there been a formal 15 evaluation of the effectiveness to NCI central IRBs? 16 DR. PATTERSON: Actually, I think there's 17 a study, an evaluation study under way of that program 18 now. And if I'm not mistaken -- I'm trying to think 19 of the timeframe for when that's going to come out. 20 Lynn, have you heard anything more about that? 21 MS. CATES: I haven't. I know that 22 they're working on it, but I don't know the timeframe. 143 1 DR. PATTERSON: I'm sorry that I don't 2 know that, but we can certainly find out. Jackie 3 Goldberg is, as I think many of you know, the 4 administrator of the program and she'd be more than 5 happy to I know at some point come and talk about 6 that. And so we can certainly make that arrangement. 7 MS. SELWITZ: Thank you. And you're in 8 the process of setting up a centralized mechanism 9 within the VA. And have -- are there any aspects of 10 trying to set up a program of that type that you'd 11 like to share with us? Things that you see as 12 extremely problematic in getting it set up, beyond 13 anything -- just the practical aspects. And also, 14 what did you -- I'm trying to figure out the purview. 15 I mean, I think some of it on central -- 16 that are government run central, like the NCI 17 pediatrics and adult IRBs, I think this issue of which 18 protocols -- I mean, there's a lot of research that 19 happens in the VA, some of which is funded by the VA 20 like your cooperative research program, some of which 21 is not. And I wondered how you dealt with the issue 22 of purview. 144 1 MS. CATES: To answer that question first, 2 what we are going to do is start with low risk 3 studies. And the VA does a huge amount of quality 4 studies, health services research studies that are 5 very low risk to human subjects. And we thought we 6 would start with those because they involve dozens of 7 sites, if not all VA sites. There are 116 VA sites 8 that do human research. 9 And so those giant studies that are low 10 risk we thought would be the greatest way to start 11 out, and then we would go on to more risky things like 12 our cooperative studies programs that might have 13 dozens of institutions doing cardiac devices or 14 something like that. But we would do those after we 15 made sure that the setup was good. 16 As far as thorny issues, the barriers, the 17 challenges that I listed here are the same ones for 18 the VA as for everyone. The one that we don't have to 19 face is liability. We've looked into that with our 20 general counsel and that's not a problem for us. But 21 the -- I think the two biggest challenges for us I see 22 going forward are local accountability to make certain 145 1 that there's somebody on the ground who looks at what 2 is going on. 3 We're blessed in the VA in that we already 4 have a system of research and development committees 5 at every site that does research. And so we will 6 probably use that mechanism. And for smaller sites 7 that use another facility's research and development 8 committee, we feel that it will probably be more 9 doable for them to have a designated representative 10 than to create a whole IRB, to put together all the 11 infrastructure for an IRB. It would be easier for 12 them to have a compliance officer or somebody like 13 that who specializes in this kind of activity. 14 The other is community attitudes, make 15 sure they've been taken into consideration. I think 16 we can do that with disease-specific representatives. 17 I think we can handle that. 18 MS. SELWITZ: What about at affiliated 19 sites? 20 MS. CATES: And that will be a very 21 interesting issue. We definitely -- she's at one of 22 our affiliated sites. We definitely need to work with 146 1 our affiliates to make sure there's a smooth 2 transition here. 3 DR. PRENTICE: Felix. 4 DR. GYI: In the interest of again just 5 complete disclosure, I think everybody knows this 6 already. Chesapeake is a subcontractor for managing 7 the NCI's central IRB, and there are some lessons 8 learned from that that I think would be beneficial in 9 moving forward. There are a couple of points to keep 10 in mind. NCI's program is currently still a pilot 11 model. 12 I mean, it's not a formalized model, but 13 there are lessons to be learned and applied as we 14 moved forward. And one of the lessons, Dr. Cates 15 you've already pointed out, which is that duality of 16 responsibility -- who has responsible? There's a 17 central IRB serving has oversight have complete 18 responsibility or do they have partial responsibility? 19 And if that's the case, what is -- how is it shared? 20 And I think that that speaks to your issue of 21 liability. 22 If I could just share with you that the 147 1 independent IRB model where we assume complete 2 responsibility and the liability may be a path that 3 you might want to follow with appropriate 4 administrative designees on the ground to address some 5 of the local issues that are of concern. So I think 6 that's one of the things that are being considered. 7 If you were to take a look at liability 8 from the perspective of financial or legal litigation 9 liability, there are just this year some insurance 10 products that are available through Lloyds of London 11 that addresses some of these issues. So I think that 12 those are also ways of mitigating some of the concerns 13 that you might have. So let me stop with that. 14 MS. CATES: Those are excellent 15 suggestions, and we're very pleased that we have some 16 very wonderful attorneys who will be attending the IRB 17 invitational workshop who will look at liability in 18 particular. But thank you; those are excellent 19 suggestions, Felix. 20 DR. PRENTICE: Celia, did you have your 21 hand up? 22 DR. FISHER: Yes. First of all, I agree 148 1 with Ada Sue; the presentations have been wonderful -- 2 very informative and so well organized and obviously 3 with a lot of background. 4 I think that centralized IRBs are a very 5 critical issue for us to address. It comes up in 6 almost every single issue that we begin to address the 7 issue of centralized IRBs comes up. And I agree with 8 Felix that perhaps SACHRP's greatest contribution to 9 this might be to provide local IRBs for example with 10 guidance as to how they should proceed with respect to 11 these centralized IRBs. 12 I guess my question is: it seems to me as 13 I'm trying to think of how we could address this as 14 SACHRP that until we have the models, alternative 15 models of what centralized IRBs are, both the private 16 model and the government model, and within those 17 models whether or not -- what role the local IRB is 18 supposed to play in that. It's very difficult of us - 19 - I think for us to provide the guidance, or even 20 begin to work on it. 21 So I would ask what your timeframe is that 22 you would think that SACHRP, if we chose to pick this 149 1 up, would have adequate information to kind of pursue 2 this? 3 MS. CATES: Great. And I would like for 4 Bern to pitch in here as well. The workshop is going 5 to be in November, and we would provide a report to 6 SACHRP hopefully within a couple of months of that. 7 Is that reasonable, Bern? And then have a public 8 meeting to follow again shortly on its heels, perhaps 9 in the spring or -- late spring perhaps. 10 We don't expect you to do anything until 11 we have done this homework for you because we think 12 that your time is so valuable; we'd like to provide 13 you as much of a straw man as possible for you to 14 proceed. Bern, did you have anything? 15 DR. PRENTICE: Bern and then Susan. 16 DR. SCHWETZ: The only thing I would add 17 is that whatever the report is that comes out of the 18 workshop will come to SACHRP. And that will be an 19 opportunity for you to respond and to endorse or 20 whatever you want to; some particular aspects of the 21 report will come out of this workshop. That will be 22 taken into account as we plan the public meeting. 150 1 So I think the SACHRP response to the 2 report that's submitted from the workshop will be part 3 of the knowledge that exists when the public meeting 4 occurs. We would welcome all of you to be part of the 5 public meeting. 6 DR. PRENTICE: Susan. 7 DR. WEINER: I guess I have two questions. 8 One is: what happens after the public meeting if 9 SACHRP is providing input before? The second is, I 10 guess for this afternoon. 11 MS. CATES: There is no question in being 12 down and dirty and up to my elbows in creating a 13 central IRB that it's a very complex subject, and 14 there's not just central IRBs, but other alternative 15 models to look at it. And so I think there's going to 16 be a lot of work to be done over a long period of 17 time. 18 As was already mentioned, NCI's central 19 IRB is still a "pilot" even after all this time. So 20 I think that we'll have a straw man after the meeting 21 in November. That report will come to you guys. You 22 will tweak it. It will go to a public meeting. And 151 1 I think that at various points local institutions are 2 going to feel comfortable jumping in, feel like they 3 have enough information to move forward. But it's 4 going to be a moving target. 5 DR. WEINER: I guess my question was: is 6 it appropriate -- and this afternoon's question is: 7 is it appropriate for a guidance to come out of OHRP 8 based on this whole process after the public meeting? 9 MS. CATES: Is that what we're -- 10 DR. PRENTICE: I think that what we want 11 to do is have the report from the working group, 12 consider it at SACHRP; have the public meeting; and 13 then decide what we want to do to push this process 14 along. One more question; that's it. 15 MS. SELWITZ: And this is just a quick 16 comment since I won't be on SACHRP when this happens. 17 I think what's very important is that there be -- that 18 practical alternative models are developed. A series 19 of alternative models, not just one or two. And I 20 don't have time now because our 12 minutes are up, but 21 we all know what the barriers have been. 22 I mean, I even thought when we had our 152 1 panel, when everybody kept saying, "Why don't 2 institutions do it?" I think it's pretty clear why 3 institutions don't do it, and I think that has to be 4 addressed in a variety of models. Because I think 5 there's a lot of support for it; it's just that the 6 models that have been offered have not addressed some 7 of the concerns that you find at the local level. 8 MS. CATES: And that's what we intend to 9 do at the IRB workshop, is to flesh out these models 10 and make them more doable and have some authoritative 11 attorneys, et cetera involved, to provide guidance as 12 to how to overcome these barriers. 13 DR. WEINER: When is the evaluation of the 14 NCI CIRB due? Does anybody know? 15 DR. PATTERSON: I said I'm not really sure 16 of, but I can find out for you. 17 DR. PRENTICE: Okay. Moving on. 18 Evidence-based practice. Questions. I'm going to 19 allow somebody to begin before me. Susan, you had 20 your hand up. 21 DR. WEINER: I thought your presentation 22 was absolutely fascinating. And two things occurred 153 1 to me. One is that that you're kind of -- the fantasy 2 includes creating a sort of professional -- a 3 discipline. And there has to be private sector 4 involvement in that and some sort of professional 5 association and some external driver to that that's 6 privately driven and not SACHRP. That's not to say 7 that SACHRP might not have a role. 8 But my second point is that from the 9 public's perspective one would really ask what the 10 federal government has done to use its own resources 11 to answer some of these questions to frame -- to shape 12 the field to answer some of the basic ideas that you 13 threw out first before there was an attempt to go -- 14 to broaden the discipline. And I don't know where the 15 appropriate vehicle is, but it might be monitoring; it 16 might be OIG, I'm not sure. 17 DR. FLANZER: There are two parts to your 18 question. Let me deal with the one that seems the 19 easiest first. The external partners are going to be 20 very important if we could pursue developing this new 21 discipline, which I'm not so sure is a new discipline 22 but it's a coalescing of a variety of interests that 154 1 are kind of spread out right now. 2 I think that PRIM&R and ARENA are a 3 natural partner in this, the Applied Research Ethics 4 National Association. I think that some of the 5 professional associations who have codes of ethics 6 about researchers are other possible partners. So I 7 think there -- you're very correct; it's very 8 important even if this were a federal research program 9 to develop it with public partnership, with 10 stakeholder input. I think the partners are out 11 there. I think we just have to kind of round them up 12 around this issue. 13 As to why we haven't used more of our own 14 information to answer some of these questions 15 ourselves, I don't have a good answer for that. I 16 think those of us who are human protections 17 administrators in our own agency do a lot of this kind 18 of work and we call on one another to say "What have 19 you read? What have you found? Who should I ask?" 20 But it's sort of the Delphi technique. 21 You know, you go to the person that you think knows 22 the most; you ask them and they send you to the person 155 1 that they go to. So there -- and there are textbooks 2 about human research protections and there are 3 conferences and the workshops, but there's not this 4 coordinated overview that creates an evidence-base. 5 DR. WEINER: NIH has an internal working 6 group on bioethics that meets. It's essentially a 7 seminar. Is that a small place to begin, that kind of 8 approach? 9 DR. FLANZER: Yes. The bioethics 10 department at the Clinical Center is an excellent 11 place to begin, but I do social and behavioral 12 research and it doesn't always fit our models. 13 DR. WEINER: No, no, no. This is an 14 informal piece; it's not -- 15 DR. FLANZER: The interest group? Yes. 16 That would be a very good place to start this 17 discussion about partnerships, too. Good suggestion. 18 DR. PRENTICE: Ada Sue. 19 MS. SELWITZ: And if this question is one 20 you don't want to answer, I will in fact understand 21 it. But do you want to talk a little bit more about 22 where you think something like this should be held? 156 1 I mean, you made reference to that, but I kept waiting 2 to hear. And if you don't feel comfortable, I 3 understand. 4 DR. FLANZER: Well, no, I don't mind 5 giving my opinion, but I want to make sure you 6 understand this is my opinion. And it's always 7 dangerous for a fed in one agency to think that the -- 8 to assign the work to another agency. You know, it's 9 kind of -- it's the easy way out. 10 But I actually think the National Science 11 Foundation because they are in the business of looking 12 at science policy type questions and have a different 13 -- a broader sense of the fields social and behavioral 14 as well as some of the clinical concerns. So that to 15 me feels like more of a discipline approach than a 16 disease-specific institute approach. Aren't you glad, 17 Peg? 18 DR. BARRATT: Excuse me? Where is the $3 19 million? 20 DR. PRENTICE: Celia. 21 DR. PRENTICE: Sally, once again, I loved 22 your presentation. I do have a number of questions 157 1 because I am a researcher. And you have been funded 2 by ORI, so -- and do a lot of this kind of looking at 3 ethics research. So I'm putting on my research hat. 4 And there's a couple of questions I think that we 5 would have to address before taking on this as a 6 SACHRP kind of activity. 7 First of all, I guess most important of 8 all is what was not included in your presentation -- 9 or at least maybe I missed it. I was trying to listen 10 for it -- was outcome measures. In other words, I 11 think for us to act, the question is: is there a 12 public concern out there or a participant concern out 13 there that something is not being done right that we 14 could have outcome measures? 15 Now, one of the problems with outcome 16 measures is that if you're basing it on violations, 17 for example, there's a very small N of violations. So 18 you can't look at that. If you simply want to look at 19 speed and how adequately paperwork is being done, that 20 might be important. I doubt that has a public 21 perception of importance. 22 So one of the critical aspects would be to 158 1 identify what is the nature of the problem that the 2 outcome measure should be looking at that would have 3 an effect on the public's trust in IRBs or 4 participants being about to utilize IRBs. 5 For example, you know, the extent to which 6 -- I could see one outcome measure, although once 7 again, I think the population samples would be -- the 8 Ns wood be so low that we wouldn't get any significant 9 results. But how many participants actually make use 10 of calling the IRB person about protection of human 11 subjects? To me, that might be an inexpensive but 12 kind of immediate kind of survey study that you might 13 do with the heads of IRBs. 14 I think it's also important in making this 15 kind of a proposal to distinguish between outcome and 16 process. Outcome measures are results. A lot of what 17 you were talking about was process evaluation. How 18 does the process go? And once again, I think it would 19 be critically important for us to identify where a 20 problem lays. Where is that problem that would be so 21 important to address now? 22 And then I think the other two issues that 159 1 would need to be addressed is in terms of quality 2 assurance, it seems to me -- and I think we had this 3 discussion when we were talking about accreditation 4 and whether or not we should recommend an evaluation 5 of the accreditation process, was that number one, 6 accreditation is supposed to -- I mean, ideally is 7 going to create more consistency and best practices; 8 and number two, that it's still too early to evaluate 9 whether or not accredited institutions are doing 10 something -- once again, we get to the outcome measure 11 -- that's any different from non-accredit. 12 And I think as a researcher I would say 13 it's confounded by money, how many research projects 14 are coming in. So it would be very difficult to 15 really evaluate as a researcher to the extent to which 16 the accreditation process is making a difference. 17 And then I think the final point that 18 would have to be raised is what would be the 19 difference between this initiative and those RFPs that 20 are going out from ORI and others with respect to 21 conducting research on the research review process. 22 DR. FLANZER: Do you have an add-on 160 1 question to that list? 2 DR. WEINER: It is not an add on. I think 3 that there's certain outcome measures that pop out 4 from the public perspective immediately that also 5 could be answered internally, like the public 6 representatives on the IRBs that were doing the 7 research. Or how long it takes to review research 8 projects. Those are of immediate and practical 9 interest to the public. 10 DR. FLANZER: I think, Celia, that I saw 11 my presentation not as -- what I defined as my goal 12 was not to really start a list of measures. I think 13 that's a very appropriate thing for SACHRP to do. And 14 I agree with you: the tension between process and 15 outcomes is really symbolic of the tension in the 16 field. 17 The ex officios have spent a lot of time 18 under Bern's excellent direction trying to identify 19 the sources of risk in the human protection program in 20 the enterprise writ large. And looking at the federal 21 vehicles that speak to those sources of risk. So IRBs 22 present a source of risk and the FWA is a response to 161 1 that. And falsification, fabrication of plagiarism, 2 represent a source of risk, and ORI looks at that. 3 So one of the ways of selecting outcome 4 measures feeds back onto identifying the places of 5 risk that aren't yet addressed. And one of the ways 6 to identify places of risk that aren't addressed is to 7 start gathering information about where these 8 intersections -- so I agree with you, outcome measures 9 are a big challenge in this area and something that I 10 think SACHRP could add considerably to that 11 discussion. Accreditation, I only chose that as one 12 of the sample things that we could -- that certainly 13 represents a variable in the enterprise that we might 14 look at if we wanted to. 15 And I do think the question of public 16 interest is a compelling one. These are federal tax 17 dollars being spent, and unless there is public 18 interest to support this notion, it's probably not -- 19 it may not merit the investment of dollars. But the 20 public interest follows disasters, and we -- I'm 21 trying to think of this as a way to get ahead of the 22 next disaster. Prevention. 162 1 DR. PRENTICE: Okay. Thank you. Let's 2 move on now to Deborah and exemptions. Ada Sue, I 3 believe that you had a question. Why don't you lead 4 off? 5 MS. SELWITZ: Deborah, and I'm not sure 6 this is so much of a question for Deborah, but a 7 comment to you and to Felix. It seems like to me the 8 issues being raised here about the exemption 9 categories are going to be the kinds of issues that 10 Subpart A Subcommittee will be looking at. And we'll 11 eventually address exemptions. And I would think that 12 this is something that fits nicely in that area 13 because -- and they're tough issues, I might add, on - 14 - and it's one we struggle at the local level, but I 15 thought the panel that SACHRP had earlier on quality 16 assurance issues and what is research and what is not 17 is at the heart of this. 18 And so I wanted to thank you for your -- 19 it's not like I sat here and knew answers on what I 20 thought we should do, but I do think it's something 21 that fits with what SACHRP is doing, and certainly 22 fits with the Subpart A Subcommittee. 163 1 DR. PRENTICE: You're quite correct. We 2 fully expect the Subpart A Subcommittee to consider 3 the definition of research, distinguishing research 4 activities from quality improvement activities; to 5 look at exemptions in all aspects -- should they be 6 revised be clarification?; expanded, what have you. 7 So yes, that's a charge that the Subpart A 8 Subcommittee has; they've just had time yet to pursue 9 it. 10 But if there are any other questions you'd 11 like to ask Deborah, please do so now. This is -- we 12 can certainly assure Deborah -- we can't assure 13 everybody else up there that we are going to be 14 pursuing your concerns already on a subcommittee. It 15 remains to be seen what we do relative to the other 16 areas because obviously SACHRP can't do everything. 17 And you know we have to prioritize as you do as well. 18 Celia. 19 DR. FISHER: I also think this is 20 something critical that both the quality assurance and 21 the exempt is something critical that SACHRP needs to 22 look at. What I didn't get from your presentation, 164 1 Deborah, which I also enjoyed very much, was what is 2 the ethical reason for expanding the exempt category. 3 My understanding, and perhaps this is 4 wrong, my understanding of some of these exempt 5 categories is -- the ethical rationale to me would be 6 that there are sufficient protections for participants 7 in place that IRB review would not be necessary. 8 Other than that, for convenience sake, 9 I've seen too many things and have also been 10 consultants in terms of public health and social 11 service research where it's a very difficult issue to 12 figure out what is part of the research, what is not 13 part of the research, and what are the rights of the 14 participants. 15 For example, individuals that receive 16 social services. Are their records -- how much can 17 you use their records to do what's quality improvement 18 or quality assurance? When does that shift to 19 research? When do they understand whether or not they 20 have some kind of right to say, "I don't want to be in 21 that part of what you're looking at. I don't want to 22 allow the research center to look at my records, even 165 1 though I'm part of this social service or public 2 health program." 3 So what I'd like to get from you is what's 4 the overall ethical framework that is the rationale 5 for expanding this exempt category in public health 6 research? 7 DR. HOLTZMAN: Well, essentially it's to 8 reduce some of the regulatory burden, you know, the 9 title of my presentation. And again, it doesn't mean 10 there wouldn't be ethical considerations in public 11 health activities or public health practice that's not 12 research. 13 And certainly something that's research 14 would go for IRB review. So it's not to get out of 15 having something reviewed by the IRB; but it's to not 16 go the other way and have things reviewed that really 17 don't need to be reviewed, that can be exempt. Again, 18 not -- you know, it's still not going to harm the 19 participant. I mean, that's not something we want to 20 do. And maybe there needs to be some sort of program 21 or regulation in place to deal with all of those 22 practice activities, which we don't have yet. 166 1 DR. FISHER: Can I just follow for a 2 minute? I think what we would need -- I mean, it 3 seems to me you've got a lot of important 4 organizations behind you, people that do good work. 5 It seems to me that there needs to be a rationale for 6 why that's not simply regulatory burden. 7 And for each of the types of examples that 8 you gave, there needs to be not only a reason why, but 9 also evidence that participants are protected. 10 Because one is assuming -- when you say that of course 11 research would be reviewed, but at the same time your 12 proposal is asking to not call certain things research 13 under federal regulations. 14 So just from my perspective, a supplement 15 to your report would be the rationale for each of 16 these exemptions as well as why we should consider 17 individuals that might be part of this type of 18 research adequately protected in terms of somebody 19 determining whether or not their rights -- whether or 20 not they are a participant or not, number one. And 21 whether or not their rights are protected. 22 DR. PRENTICE: Any other questions? Ada 167 1 Sue. 2 MS. SELWITZ: One more question. I mean, 3 and again, this just shows how na‹ve I am about 4 surveillance research or public health activities. 5 What kind of ethical standards and framework exist? 6 Because I mean, there's -- much of what you do now 7 does not come under the IRB or is exempt. What kind 8 of ethical framework, guides, research design, and 9 those areas that don't currently fall under the IRB 10 are eligible for exemption? 11 DR. HOLTZMAN: Well, there currently isn't 12 one. I mean, at least there's nothing explicit. So 13 I mean, that's part of the issue. Do we need to have 14 a program that covers all of our activities, whether 15 they're research or practice? 16 DR. PRENTICE: Okay. We have a minute and 17 a half. Anybody have another burning question that 18 you could ask any of the panel members? All right. 19 We're going to adjourn for lunch, but before we do so 20 a couple of comments. One, for SACHRP members, this 21 should be a thinking lunch -- not a working lunch, a 22 thinking lunch. Because you need to think about 168 1 priorities, not only priorities presented by our 2 panelists, but also priorities that you think that 3 have not yet been presented or perhaps have been 4 discussed in the past and we sort of have tabled them 5 and you want to raise those now. This is your 6 opportunity to do so, in the next afternoon session. 7 So I want you to think about that. 8 Secondly, I want to move up the public 9 comment period to immediately after lunch. We'll 10 still retain the public comment period at 4:15 if 11 we're not adjourned by then, but for anybody that 12 would like to address SACHRP, please consider doing so 13 at right around 1:30. So we're going to go ahead and 14 take lunch between 12:30 and 1:30. We'll try to 15 reconvene shortly after 1:30. Okay. 16 And I would like to thank the panelists, 17 and lets give them a round of applause. 18 (Whereupon, proceedings in the above- 19 entitled matter went off the record at 12:31 p.m. and 20 resumed at 1:34 p.m.) 21 DR. PRENTICE: Thank you everybody for 22 coming back on time. You're really getting very 169 1 compliant with time requirements. This is new 2 behaviors I'm noticing. 3 What we're going to do for the remainder 4 of the time this afternoon, however long that actually 5 lasts, is to consider future SACHRP priorities, both 6 within SACHRP itself as well as a consideration of the 7 presentations by our ex officios. 8 And before we do that, however, I have 9 moved up the public comment period. And I have three 10 individuals who would like to address SACHRP. I will 11 call them up in order, and when you come up please 12 state your name for the record and your affiliation. 13 And try to limit your comments to not much more than 14 five or so minutes. Okay. 15 Peter Kim. 16 PUBLIC COMMENT 17 MR. KIM: Thank you, Dr. Prentiss. My 18 name is Peter Kim. I'm regulatory counsel, Quorum 19 review IRB. We are an independent IRB situated in 20 Seattle, Washington. We primarily conduct IRB review 21 of FDA regulated or industry sponsored research, and 22 the large bulk of that is multi-center research -- 170 1 multi-center site research. 2 First, let me -- I wanted to express my 3 pleasure in addressing this group and all the members. 4 And I'm very delighted to see as one of the 5 considerations for priorities the consideration of 6 using a centralized review process for multi-center 7 research. I'll keep my comments very cursory. 8 I only wanted to bring to the group's 9 attention but I think that the FDA put out a guidance 10 in March of this year on using a centralized IRB 11 review process for multi-center research. And I think 12 it really discusses well and presents some good 13 suggestions or recommendations and workable models for 14 some of the challenges in conduct multi-center 15 research through a centralized review process, 16 particularly local accountability as well as 17 considering community attitudes and participant 18 population concerns. 19 I want to commend Dr. Cates on her 20 presentation, and I'm very delighted to hear that 21 there's to be an IRB workshop discussing and sharing 22 some of these best practices for traditional IRBs, 171 1 that is, institution IRBs to take into account 2 elements of centralized review to promote quality, 3 human subject protection, while enhancing the process. 4 And I'm delighted and I very look forward to hearing 5 SACHRP's and ultimately OHRP's recommendations as to 6 some of these best practices as we move forward. 7 DR. PRENTICE: Thank you, Peter. Now we 8 of course agree with you that it's a very important 9 topic. As I indicated earlier, the workshop arose out 10 of a panel discussion that we had with regard to 11 central IRBs which of course include independent IRBs 12 like Quorum. And the way we conduct research these 13 days as multi-center clinical trials is not like it 14 was back in the `70s. That's why we have a lot of 15 independent IRBs who fulfill a very valuable role, 16 whereas back in the early `80s there were only a 17 handful. 18 Next I would like to invite Dr. John 19 Mather. 20 DR. MATHER: Thank you, Ernie. Dr. John 21 Mather. I'm vice president with Chesapeake Research 22 Review which is an independent IRB. I just want to 172 1 make a couple of comments on two different areas that 2 were presented this morning, each of which I think are 3 very, very important. I just want to concentrate some 4 remarks on a couple of them. 5 One is in regard to the issue of the 6 central IRBs, I guess conceptually we have moved from 7 just thinking of IRBs as being the only way in which 8 we protect human subjects. We put it in a broader 9 context of an institution of human research protection 10 program. And the accrediting bodies think in that 11 terminology. 12 So when the focus comes onto the IRB, I 13 begin to think about, "Well, yes, that's okay, but 14 who's overall responsible for what is going on in the 15 protection of the human subjects in the broader 16 context in human research protections?" I think it's 17 difficult and I think Lynn this is going to be the 18 challenge, is figuring out who's accountable for what 19 in this structure. 20 I think we've got some models. I think 21 the independent IRBs represented by Chesapeake or 22 Western IRB have worked through some of these issues, 173 1 especially with respect to multi-site. What I'm also 2 noticing is an increasing interest by academic medical 3 centers to pass out or turf out some of their work 4 that is specialized so that if they feel like they're 5 not that good in drugs and devices or biologics, they 6 will find an IRB that on their behalf can do that work 7 and then list it under their FWA. 8 I'm very aware of the IRB out on the west 9 coast that really simply is a hospice IRB. They do 10 hospice work and many, many people utilize that IRB 11 and list it on their FWA depending on what institution 12 you're coming from. 13 I think this notion of the designation of 14 lead local IRBs, and you gave the example of the MACRO 15 which I believe is in Chicago but I'm not sure where. 16 But there are other places that are doing similar kind 17 of regional consortia. I'm aware of Michigan State 18 University with its way in which the university's IRB 19 has become the focus for several hospitals and even 20 the CRO has now come into that fall. 21 So again, it's a different kind of model 22 that works on a regional basis which begins, I think, 174 1 to address one of the issues of concern that I have 2 heard. And that is how does a central IRB take into 3 adequate consideration the local culture, whatever 4 that is? I'm still not sure when I get that thrown 5 back to me exactly what they mean by "the local 6 culture." 7 Is it just simply some acknowledgement 8 there are differences in which IRBs do work and we 9 can't expect any great consistency across IRBs? And 10 an excuse for that, "Oh, it really means something 11 more in depth than that." And I would hope that your 12 meeting will get into that in a little more detail. 13 And I just would like to put it in a 14 broader context. The notion is I guess when we're 15 protecting human subjects, is this an HRPP and it's 16 not just simply the IRB and how the other parts come 17 into play in that regard. 18 Then the other I just want to address some 19 remarks to is the issue of program evaluation or 20 quality assurance and quality improvement. For many 21 years I've heard people say, "Well, if anything 22 involves human subjects," almost de facto it comes 175 1 under the rubric of either the HHS regs or FDA. 2 Well, leaving FDA regs aside for the 3 moment, under the Common Rule, but what really, really 4 comes under that umbrella? I remember very well 5 hearing so much about operations research. Well, a 6 lot of operations research collects data on human 7 beings, including, I think, which you were alluding to 8 earlier, was employee surveys. Well, the employee 9 surveys which are hopefully can prove the operation of 10 the organization necessarily represent research. 11 One the one hand you might say, "Yes, they 12 do. They're collecting data on human beings. There's 13 privacy concerns here, and there's confidentiality 14 concerns here." But is it really research? So 15 whenever I hear the word "operations research" I sort 16 of step right back and to myself say, "Well, wait a 17 minute. Is it really research in the context of the 18 way in which we construe the Common Rule?" 19 We heard I think two or three meetings ago 20 a couple of very interesting presentations. One from 21 the public health side in trying to make this 22 distinction between public health practice and 176 1 research. And if we go down that track, I think it's 2 worth re-looking at that information again because I 3 have found that particular paper that was distributed 4 at that time very, very helpful in making this kind of 5 distinction because what I heard today was something 6 different. And that was, "Well, we ought to just take 7 the opportunity exempt category and just kick it all 8 out and put it into that exempt category, the public 9 health practice/research." 10 Well, broadly, I think just because it 11 becomes exempt as we've heard before, it doesn't 12 suddenly mean there aren't ethical issues, and there 13 isn't a concern about who is monitoring that. I don't 14 know, again going back to this concept of the HRPP, 15 whether the institution because it's decided it's 16 exempt has a clear responsibility in tracking that 17 which is now designated as exempt research. I think 18 some institutions take it on very carefully, and 19 others do not. 20 So then that rolls into that other 21 presentation we heard which involved, I think, 22 somebody who is involved in the Institute of Medicine 177 1 study and NCQA who made the assertion that anything 2 that's sort of QA/QI is the practice of QA/QI in the 3 health field, and sort of really doesn't come under 4 the rubric of being considered human subjects 5 research. 6 I think a lot of people sort of backed off 7 and said, "No, wait a minute. That doesn't really 8 fit." But making this distinction between quality 9 assurance, which again I go back to the concept of 10 operations research, collecting data for purposes of 11 it simply improving that system whether it's the VA or 12 it's a military hospital, to looking at two people who 13 have those kinds of strong programs; or in the private 14 sector. 15 If you have a QA program under joint 16 commission, does it mean therefore it really sort of 17 follows its research or when you make it the next step 18 when you're doing some comparisons and that which we 19 would call quality improvement and it really does kick 20 in to being research. 21 My point is that I think, Ernie, just to 22 say I think there's some area here in program 178 1 evaluation, operating -- whatever these terminologies 2 are, that there's some worthiness to getting it clear 3 on what really comes under the purview of being 4 considered human subjects research. Thanks so much. 5 DR. PRENTICE: Thank you, John, for your 6 always astute comments. Let me ask one question and 7 then make one comment. You refer to the hospice IRB. 8 Are all the IRB members in hospice? 9 DR. MATHER: Ernie, I don't know the 10 answer to that. This is the one out in San Diego. 11 And my understanding is that what you're alluding to 12 is are they all on the hospice program, and therefore, 13 they're on their way. No. I don't think that's 14 exactly the way it was meant to be. 15 DR. PRENTICE: That's exactly where I'm 16 going. 17 DR. MATHER: But I think your point in a 18 broader sense, again, if you have a specialized IRB, 19 what is the community it represents? If it's taking 20 your humor a little bit the other way. Does that mean 21 you should have people on the IRB who are in the 22 process of dying? Well, maybe so. I don't know. But 179 1 certainly I think we're asking the question about 2 specialized IRBs may make some sense, but increasingly 3 it's, I think, difficult for IRBs to fulfill their 4 functions with the panoply of research that gets 5 thrown at them. 6 I mean, if it's really hospice research 7 and there's a place that really understands how this 8 plays out, it may be worth an academic medical center 9 saying, "Well, we want to add that IRB to our FWA 10 because this is the kind of research they really 11 understand." Maybe there's a place, you know, Susan, 12 for pediatric research. If your institution is that 13 good at it, maybe everybody in the Boston area ought 14 to be listing you as their IRB and working out some 15 MOUs so you get some business in that regard. 16 MS. KORNETSKY: We tried that. 17 DR. MATHER: You tried that? I'm trying 18 to point out the generic concern, and that is, how do 19 IRBs in an academic medical center with all the 20 variety of research that gets thrown at them really 21 have the expertise. They can use sector reviews, 22 consultants and all the rest. 180 1 But if there's a place that naturally does 2 this work and does it very well, maybe that's a place 3 that's worth going for. And it's a variety and brand 4 of, I think, using a centralized IRB by saying, "We 5 will use that central IRB." 6 DR. PRENTICE: One of the outcomes that 7 I'm hoping for from the AAMC-ASCO workshop on IRB 8 models is to come up with some guidance as to how 9 academic institutions form a partnership with either 10 a central IRB or an independent IRB like Chesapeake. 11 Part of the reticence of a lot of academic IRBs is 12 they don't understand this concept of partnership. 13 There's no clear understanding of the role 14 of the central IRB versus the role of the local 15 institution, how this central IRB or independent IRB 16 fits into the HRPP, which you mentioned. And I think 17 that that's -- in my view, one of the more important 18 outcomes of this conference, to come up with how 19 should that model look like to make it an effective 20 model. 21 Your comments about the distinction 22 between research and program evaluation and quality 181 1 assurance projects, of course, that's something that 2 we talked about on our panel, as you mentioned. It's 3 certainly something that will be considered by Subpart 4 A eventually. 5 And I know that OHRP has an initiative to 6 try to look at that exact issue as well. And it's 7 something that we do need to tackle. And hopefully 8 within the not too distant future we'll have some 9 guidance because speaking on my behalf, in my IRB, we 10 have these kinds of problems trying to figure out what 11 comes under our purview and what does not. 12 So I thank you, as always, for your 13 comments, John. Our next speaker would be Dr. John 14 Mills from the Mayo Clinic. Dr. Mills. 15 DR. MILLS: Thank you. My name is John 16 Mills, and I work at the Mayo Clinic. I actually have 17 two comments today, one to follow-up on some 18 discussion yesterday regarding the nice presentation 19 on the proposed guidelines for adverse event 20 reporting. And a couple of the committee members, Ada 21 Sue and Susan I think in particular, expressed our 22 views at Mayo of those guidelines, and I just wanted 182 1 to reiterate some of those comments because I think 2 they bear repeating. 3 That is, we appreciate OHRP's work. We 4 think it's a great step in the right direction to come 5 up with a more rationale way of dealing with adverse 6 events, particularly in multi-center trials where it's 7 an outside or external adverse event. But we'd also 8 like to reiterate the plea to FDA to come on board, to 9 come with something that can be harmonized with the 10 OHRP guidance. 11 We recognized pretty quickly that without 12 that, the work of OHRP is probably going to be for 13 naught. And actually, we had an experience similar to 14 what Ada Sue expressed at her institution, where she 15 described their efforts to come up with a more limited 16 adverse event reporting guideline, and found out that 17 it was naught. 18 We did the same thing. We've told our 19 investigators and have a policy limiting or allowing 20 them to report less or report differently to us 21 adverse events that occur outside of Mayo. What we 22 found is it had no effect, in large part because 183 1 industry sponsors, investigators, everybody, is so 2 used to the old system and pays close attention, 3 rightfully so, to what FDA says. 4 So the message we've gotten loud and clear 5 is, it's a good direction to be going. And we were 6 encouraged with the comments from FDA and from other 7 folks that that's where they seem to be going. But we 8 just wanted to reiterate Mayo's support for moving in 9 that direction. 10 The other comment, the second area I 11 wanted to comment on had to do with the discussion on 12 central IRBs, and again dealing with multi-site 13 trials. Again, we at Mayo see this as a positive 14 opportunity for a step in the right direction. And 15 again, Ada Sue's comment, I think, was exactly what I 16 was thinking, which is it's a good opportunity but I 17 think one of the things that we'd ask that the group 18 that will be getting together in a couple of weeks to 19 think about, and this committee to think about, is as 20 you look at what comes out of that group is not only 21 what a central IRB or some mechanism can do to make 22 sure that they're compliant with the regulations and 184 1 ethical guidelines and all, but also to try to figure 2 out how those central mechanisms might break down the 3 barriers that academic medical centers have to using 4 central IRBs. 5 We've talked a lot about it at Mayo, and 6 I have no question that a central IRB could be put 7 together to do a perfectly good job of reviewing and 8 approving research in full compliance with the 9 regulations. My biggest concern is how we would then 10 incorporate that into what we do at Mayo, and 11 hopefully come up with a way where even though there 12 might be a single IRB review, that that could somehow 13 be tailored to, for example, unique policies that we 14 have at our institution that other committees and 15 powers that be at Mayo are going to mandate in the 16 research. So somehow having a central process but 17 that can still recognize institutional differences. 18 Thank you for your time. 19 DR. PRENTICE: Thank you, John. And thank 20 you for coming all the way from Minnesota to listen to 21 our deliberations. As I indicated, I think yesterday, 22 most of the people are feds here, not that they're not 185 1 welcome -- but they're still feds. So it's nice to 2 get people from the IRB community as members of the 3 public, so thank you for coming and thank you for 4 commenting. 5 MS. SELWITZ: I want to go on the record 6 and say I liked his comments. 7 DR. PRENTICE: Okay. All right. Does any 8 member of SACHRP want to either comment or question 9 any of the members of the "public" who came up here to 10 talk? Felix. 11 DR. GYI: Given that this might be my last 12 meeting, I guess I better take advantage of it. 13 There's been a lot of discussion about central IRBs, 14 and clearly we're all waiting for the meetings to take 15 place. But there are models that are quite workable. 16 Institutions, I think, have been reluctant 17 in some ways that you've described -- there are many 18 relationships that we have and other independent IRBs 19 have with institutions that are very productive. But 20 it doesn't mean that it has to be a one-sided type of 21 abdication of responsibility to a central IRB. The 22 concept of a concerted human research protections 186 1 programs, I think, mandates that institutions retain 2 a certain amount of responsibility in overseeing what 3 they have a chance to oversee and maintain that level 4 of responsibility. 5 And so the role of an independent or a 6 central IRB in working with an institution is quite 7 doable. And I would encourage all of us, especially 8 Dr. Cates, as you're thinking about this, I think that 9 there are very few models. I don't think that there 10 are a handful of models even that would work well 11 given the regulatory structure that we have. 12 But clearly, there are very workable 13 models that we ought to simply bring forward as 14 quickly as possible because clearly the demand is 15 there. Thank you. 16 DR. PRENTICE: Any other comments, 17 questions? Yes. Susan. 18 DR. WEINER: Just as a follow-up, it seems 19 to me that it would make sense when one discusses the 20 alternative models to say something about the 21 circumstances in which they'd be appropriate to use. 22 Some suggestions or guidelines or whatever as a way of 187 1 reassuring institutions and having institutions think 2 through whatever challenges they may face. To divert 3 it from the concept that it's an all or none process, 4 and that there's only central or local, as a way of 5 reinforcing that. 6 DR. PRENTICE: Okay. I obviously agree 7 with all of the comments. I'm reminded about the time 8 that I went to the University of Rochester after the 9 death of Nicole Wan in a bronchial alveolar lavage 10 study. And I was part of an OHR -- I guess it was 11 OPRR site visit team that went in. And they had 12 contracted with Western IRB. 13 Basically, over the weekend, prior to our 14 visit, because they were going to be shut down by FDA 15 -- and when I went in, and I think I reflected the 16 attitude of my OPRR colleagues, that I was opposed to 17 the utilization of an independent IRB by an academic 18 institution. And I said so publicly to the president 19 of Western IRB, much to her, I'm sure, chagrin and 20 disappointment. 21 But since then, I've found out an awful 22 lot more about how these models can work and how they 188 1 can be effective. And really, Western was the first 2 one with Rochester that had this marriage, so to 3 speak. And then since then, we've had a lot of 4 examples of ways in which central or independent IRBs 5 can work very effectively with academic institutions. 6 So again, I'm looking forward to the 7 outcome of this workshop in terms of the issuance of 8 guidance, a report that can be considered by SACHRP in 9 the future. 10 All right. Now, the rest of the day is 11 going to be devoted to discussion of future SACHRP 12 priorities. And I indicated before lunch, they're not 13 limited to the four topics that were presented this 14 morning, one of which we've already started to 15 discuss, that being IRB models. 16 But before we do that, I want to indicate 17 that in terms of IRB models, that's something that is 18 already going to be considered by the AAMC-ASCO 19 workshop. You already know they're going to produce 20 a report. There's going to be a public meeting. And 21 eventually, all of this will come back to SACHRP. So 22 I don't think we need to talk about what SACHRP can 189 1 do. That would not be an effective utilization of our 2 time. We can certainly discuss this, but there's no 3 point in talking about our role because we need to 4 wait for the report to come out. So I want to set 5 that as a caveat. 6 Secondly, in terms of Deborah's 7 presentation from the CDC perspective about 8 exemptions, I think that's also going to be pursued by 9 not only OHRP but also the Subpart A Subcommittee, so 10 again, I don't think we need to think about, well, 11 what can SACHRP do. Well, we're already doing 12 something in that area. So think about that as we 13 progress in our discussion. 14 So that leaves two areas, international 15 research and we've had one panel. We had a lot of 16 issues raised by the panelists, and we sort of just 17 kind o put that on the table and left it there. That 18 was, as a matter of fact, some of our -- one of our 19 first panels, the first or second meeting that we had. 20 And then the second area is evidence-based 21 practices that Sally talked about, and how do we get 22 data about the effectiveness or lack of effectiveness 190 1 of HRPPs and IRBs, et cetera. 2 So having said that, the floor is now open 3 for discussion among yourselves. You can also direct 4 questions if you wish to the ex officio members. And 5 we'll follow the normal format for organization. 6 Please raise your hand so you get recognized. And if 7 you want, we can stick with one area first. Or do you 8 just want to have a -- how would you like to do this? 9 You just want to start asking questions? What would 10 you like to do? You're shaking your head yes; what 11 does that mean? 12 DR. WEINER: I say we put ideas on the 13 table. 14 DR. PRENTICE: Just put the ideas on the 15 table about everything? Okay. Susan, you're up. 16 IDENTIFICATION OF FUTURE SACHRP PRIORITIES, 17 DISCUSSION 18 DR. WEINER:. In thinking about this over 19 lunch, I came back and reread the charter. And 20 understanding that two of the topics that were 21 discussed this morning are already in process. And 22 there are two things that jumped out at me from the 191 1 charter. 2 One is another special population which we 3 have not yet addressed, and that is the decisionally 4 impaired. And the second is that the committee is due 5 to expire October 1, 2006. So I don't know how -- 6 what would be appropriate to take on as a major new 7 project if that's a real date. Or whether we could 8 take on something as enormous as international 9 research with the promise that we would be extended, 10 or not expending effort that would be futile. 11 So those are my two points. One is the 12 constraint and the other is to put on the table 13 whether the committee thinks looking at issues 14 associated with the decisionally impaired is a 15 priority. From a public perspective, I think it's a 16 priority. But let's hear what everybody says. 17 DR. PRENTICE: Okay. Kathy, are we going 18 to expire October 1, 2006? 19 MS. SLATINSHEK: I can't answer that 20 question. But I have been directed by the folks 21 downtown in our departmental committee management 22 office to start on revising the charter for another 192 1 two years after the first of the year. So that's all 2 I can say at this point. 3 DR. PRENTICE: Okay. I would be 4 optimistic that the charter will be renewed. So the 5 second point I want to make is relative to 6 decisionally impaired subjects in research. As you 7 know, a proposed Subpart E was issued, I guess, way 8 back in the `70s. It got withdrawn, never to be heard 9 from again. It's also my understanding there was a 10 lot of opposition in the mental health community about 11 those additional protections. OHRP is in the process 12 of drafting a -- what do you call it, Bern? -- a -- 13 DR. SCHWETZ: Advanced Notice. 14 DR. PRENTICE: -- Advanced Notice for 15 Proposed Rulemaking where the public will have an 16 opportunity to comment on whether or not they think 17 that we need additional rules for protection of human 18 subjects. My own personal opinion is that I think 19 it's a gap in 45 CFR 46 that I would like to see 20 filled, but we have to go through the normal 21 procedures. 22 So I think that the next step is to get 193 1 this notice issued and get the comments back. It 2 might be premature for SACHRP to take it upon itself 3 to start talking about this issue and figure out what 4 the additional protections might or should be. 5 DR. WEINER: Okay. I guess I would just 6 like to put on the table the possibility that there 7 would be an expert panel. 8 DR. PRENTICE: And expert panel on 9 decisionally impaired? 10 DR. WEINER: For us. Yes. 11 DR. PRENTICE: Irene. 12 MS. STITH-COLEMAN: I just wanted to 13 clarify that that is a joint notice, OHRP and FDA. 14 DR. PRENTICE: Okay. We'll certainly take 15 that under consideration. Celia. 16 DR. FISHER: I also think decisionally 17 impaired is a very important issue. I'm also 18 wondering -- I don't know what OHRP -- how the 19 announcement of the OHRP/FDA is going to look, but I 20 think at the moment we may not want to simply 21 dichotomize that there's a Subpart E, or there's no 22 guidance on the decisionally impaired. 194 1 And so I'd like to keep that open in terms 2 of -- I think I said this last time, but one of the 3 challenges of the Subpart E will be very much like 4 what we found in prisoners. That people who are 5 decisononally impaired are not static, that some of 6 them are transients, some of them are the potential 7 for impairment, others are decreasing competency. And 8 so I think that the definition of decisionally 9 impaired is going to be very difficult. 10 And so I wouldn't want guidance that might 11 be very appropriate given some of the other Subparts 12 not to be considered if in fact simply a new section 13 may not be as workable. 14 DR. PRENTICE: Well, there are two ways to 15 look at this issue, I think. One is you issue a 16 Subpart E which is not guidance; it's regulations. Or 17 you issue guidance which is guidance, not regulations. 18 The NIH has guidance on research involving 19 decisionally impaired people. I don't know how widely 20 disseminated that guidance was, but it's still there, 21 NBAC, same thing. 22 DR. FISHER: Well, NBAC had that, and then 195 1 what NIH came out with is very loose guidance. I 2 mean, it's not very specific. It's not step-wise 3 guidance or specific guidance. I really think it's 4 really more for -- my reading of it is you have to be 5 respectful. I mean, basically if I would put it in a 6 nutshell, that one needs to be respectful and these 7 kinds of things. So I think that the guidance is 8 important because it's out there. 9 My understanding also is that the 10 derivation of that guidance -- we're talking about 11 came out of Wendy Baldwin's office? That guidance, I 12 believe. That it was really in response to a 13 reluctance to accept the NBAC recommendations for 14 which there was a number of controversial points. 15 So I don't think we want to throw out the 16 baby with the bathwater in terms of thinking that 17 guidance is sufficiently detailed enough at this 18 moment to kind of help with all these issues. 19 DR. PRENTICE: I agree with you. I was on 20 the NIH panel that deliberated to produce the 21 guidance. I can't remember if it was post-NBAC or 22 pre-NBAC. But nonetheless, I think we need more than 196 1 what we have. 2 Let's leave it at the possibility that we 3 would convene an expert panel to address the issues, 4 and we can discuss that at OHRP and decide is that the 5 way to go, and is this the right time to go in that 6 direction. Okay. Will that be satisfactory, Susan? 7 Susan. 8 MS. KORNETSKY: Another idea, I alluded to 9 it yesterday, and it's not completely outside the 10 purview of any of the subcommittees, but I would like 11 to put on the table the issue about guidance for wards 12 of the state under the children's regs. Now, I'm 13 mindful of the fact that there may be some 14 investigation going on about that, and I want to be 15 sensitive to the timing of that. But I would like to 16 put that out there as something that perhaps the 17 Subcommittee on Children could take on. 18 DR. PRENTICE: Good idea. You are never 19 going to end your work. You know that, don't you? 20 Okay. That's not a problem. Your children's 21 subcommittee can decide what directions you want to go 22 in. We can certainly provide input as to what we 197 1 think, what OHRP thinks, but you can also come up with 2 ideas and say, "We think this is important. We think 3 we need to do this." And discuss it, and then it can 4 be put as part of your charge. Okay. 5 Felix, I saw you first. 6 DR. GYI: So we are just gathering ideas 7 right now. 8 DR. PRENTICE: That's correct. 9 DR. GYI: Well, as the committee knows, 10 Mr. Adams and I co-chaired the subcommittee on 11 accreditation very early on. And after a fairly 12 lengthy and in-depth discussion back then, which was 13 now close to two years, made a recommendation that 14 recommendations wait for a couple of reasons. One, 15 AAHRPP had been just awarded a CDC grant to look at 16 the impact of accreditation; and two, we felt that it 17 was early enough in the process that we wanted to have 18 market forces work itself out. And to help us to 19 provide some direction with regard to the 20 recommendations that we might want to make. 21 And as Dr. Schwetz reminded us, AAHRPP did 22 make the announcement that as of November 15th they 198 1 will be going out of business. Back then, we looked 2 at a range of issues -- pardon me? I am so sorry. 3 DR. PRENTICE: We know -- 4 DR. GYI: For the record, it is the 5 Partners Program that is going out of business. So 6 there is one accrediting agency. And I think that one 7 of the things that we had looked at was, what is the 8 impact of accreditation and how does it integrate with 9 some of the programs that are currently in place. The 10 Accreditation Subcommittee felt very strongly that 11 accreditation much like education and certification, 12 had a true value in the protecting of human research 13 subjects, and that it ought to be recognized in some 14 way. 15 And so I would ask this committee to see 16 if it's time for us to reevaluate that and take a 17 position to help the agencies either understand how we 18 might integrate that or how we might -- how it might 19 find a place in the human research protections program 20 in its entirety. And so I'd like to put that back on 21 the committee. 22 DR. PRENTICE: Okay. If I may, Felix, I 199 1 will share parts of your letter addressed to Bern and 2 I from Tom and you, so that we can more fully discuss 3 the issue you brought up. 4 There were three recommendations adopted 5 by SACHRP as a consequence of your subcommittee's 6 work, and they were as follows: there should be a 7 systematic evaluation of accreditation as an assurance 8 of quality research and subject protections; second, 9 develop a list of incentives to HRPPs for research 10 institutions that seek accreditation; and three, a 11 conference be organized by HHS to be held to include 12 all the major stakeholders to examine a wide range of 13 self-regulatory initiatives that have been undertaken 14 over the last five years. 15 Do I have that right? Okay. Looking at 16 the first recommendation: a systematic evaluation of 17 accreditation. That sort of dovetails with some of 18 Sally's comments during her presentation. Do you 19 think that enough institutions have been accredited by 20 now, it's basically AAHRPP because PHRP is out of 21 business, to be able to allow a valid evaluation of 22 accreditation to be obtained? 200 1 And secondly, do you know what the status 2 is of the CDC grant implementation that AAHRPP got? 3 Do know what they're doing with that? And how much 4 data do they have? 5 DR. GYI: To answer the second question, 6 I do not know what the status is because we said that 7 we would invite Dr. Spears to come back and give us 8 some information at a later point in time. And I 9 don't know what that is, and perhaps -- 10 DR. HOLTZMAN: The grant is in its last 11 year. It was funded for three years, and so it will 12 finish up next year. And what AAHRPP was doing was 13 trying to identify measures that could be used to 14 actually evaluate accreditation programs that had been 15 accredited. 16 So there's no data yet to show whether 17 accreditation is a good thing or not. But she is 18 still working on developing these measures and will 19 have a final report next year, late next year. So 20 she's still in the process of doing that. But that 21 was the focus of the grant, not to actually evaluate 22 the effort. 201 1 DR. PRENTICE: Okay. So perhaps it would 2 be premature, at least in terms of that 3 recommendation, to pursue it further until data is 4 forthcoming. Would you agree? 5 DR. GYI: I would. But keep in mind that 6 there is no data that's going to come out of that 7 particular research. Again, if I'm recalling 8 correctly, the grant was simply to look at measures of 9 impact of accreditation. So I don't think that there 10 will be any data per se. 11 DR. PRENTICE: Well, not having seen the 12 specifics of the grant, do you have any ideas about 13 how would you perform a systematic evaluation of 14 accreditation? What kind of data would you want to 15 gather? 16 DR. GYI: I've wrestled with that notion 17 for a very long time because I've often wondered if 18 what we're doing really adds meaningful to human 19 research protections, and we have those discussions 20 internally quite often. And I don't know how we will 21 measure that, so I'm looking forward to the 22 information that's going to come out of that 202 1 particular initiative. 2 I suppose if I had to give a 3 recommendation, I would ask that we at least look at 4 how we reduce some level of regulatory burden on IRBs 5 if they are accredited. For instance, is there some 6 way for us to take a position that says to both 7 federal agencies as well as sponsors because 8 accreditation is a valued concept, is there a way for 9 us to use that as a leverage point that says that 10 perhaps you don't need to do the systematic types of 11 checks. 12 As an independent IRB we get audited very 13 often by sponsors because they don't have any faith in 14 any other mechanism. And so can we then at least 15 evaluate the value and the role of accreditation in 16 that whole overall systematic evaluation process? I 17 don't know what the answer is; perhaps that is one way 18 to approach it. 19 DR. PRENTICE: Felix, I see where you're 20 going on this. You really moved into the second 21 recommendation incentives in a way for HRPPs. I mean, 22 why should an institution become accredited? Maybe if 203 1 sponsors were not placed in clinical trials and 2 institutions that were not accredited, that would be 3 one incentive. Or sponsors would be more comfortable 4 with the quality of human subject protections so they 5 would not audit as often. That's another incentive. 6 I doubt that the FDA would change their 7 bioresearch monitoring system where they've got to 8 come in every three to five years, sometimes it's 9 longer than that by the way, but it's supposed to be 10 every three to five years. I don't think they're 11 going to change that just because an institution gets 12 accredited. 13 So other than the ones you just mentioned, 14 I'm not quite sure what incentives you would use to 15 get an institution to seek accreditation. 16 And then second, regulatory burden. In 17 some ways, I'll tell you my own view, is that 18 regulatory burden in terms of doing things more 19 thoroughly and documenting more thoroughly is a 20 consequence of accreditation. It's not been 21 decreased. It's been increased without question. I'm 22 not saying that's not -- I'm not saying that's good, 204 1 I'm not saying it's bad. It's simply a fact. It's 2 been increased. 3 DR. GYI: Perhaps the approach might be to 4 take a look at how we might collaborate on how we use 5 accreditation as one of the cornerstones in our own 6 daily practice. Or maybe to have that conference with 7 stakeholders like the sponsors to get together to say, 8 "Do we value accreditation? What is the agency's 9 thinking about having to go through an accreditation 10 process?" 11 Right now, there isn't any language out 12 there that says that it is either acceptable or it's 13 good or anything that's really truly positive that's 14 visible to the industry. And so while you go through 15 accreditation, there is nothing that you get back in 16 return, at least verbally or tangibly. I will tell 17 you that because we have gone through accreditation, 18 we have seen a decrease in the number of sponsor- 19 initiated site visits to our group, because I think 20 that there is a perceptual feeling that accreditation 21 does cover certain elements that they are concerned 22 about. 205 1 But let's put it out there so that 2 everybody can see the fact that that does happen. And 3 let's move in that direction. Right now, we don't 4 have any mechanism to point to something like that 5 that says that accreditation is a good thing. Or even 6 certification or education. 7 DR. PRENTICE: Okay. There are 20- 8 something institutions that have been accredited by 9 AAHRPP. Is that correct? 10 DR. GYI: Closer to 30. 11 DR. PRENTICE: Pardon me? Closer to 30 12 now? 13 DR. GYI: Close to 30 that represent over 14 close to 100 institutions or sites. 15 DR. PRENTICE: Are in the pipeline; is 16 that what you're saying? 17 DR. GYI: No. 18 MS. CATES: I think 29 have been 19 accredited, but that includes -- those are umbrella 20 organizations for several other organizations. So it 21 ends up being 80-some-odd to 100 total institutions 22 under their umbrella right now. And then we've done 206 1 78 at the VA NCQA. 2 DR. PRENTICE: Under NCQA? 3 MS. CATES: And PHRP did 10. 4 DR. PRENTICE: Okay. Do we have enough of 5 an end to hold that conference, or do you think we 6 need to wait a while, get more information, more data, 7 more experience? 8 DR. GYI: Well, we can always wait for 9 more data. I think that that's -- that would be 10 reasonable. But how long do we wait? My feeling is 11 that we do do something before it gets too far ahead 12 of us. And accreditation is not valued in a way that 13 it probably ought to be. 14 MS. KORNETSKY: I can't -- I mean, I 15 certainly support what Felix is saying, is from an 16 institution that spent a year and a half doing this, 17 as many of us have, I think it is a good thing. And 18 personally, I think within the institution. I guess 19 I'm thinking for it to mean something, it's sort of 20 tied to sort of the outcomes of it. 21 I mean, to make the claim that we should - 22 - sponsors should only go to institutions that 207 1 accredited, you've got to prove that it's effective. 2 So I see it very interrelated, and as much as I would 3 like to do something quickly, I'm not so sure that we 4 can claim this is a good thing until we have data to 5 show that it's a good thing. 6 So it's sort of a Catch-22. As much as 7 I'd like to see something done quickly, my sense would 8 be we've got to prove it before we can claim it, 9 before we can try and sell it to sponsors, to the 10 government, to anyone. 11 DR. PRENTICE: Let's see. I've got people 12 on the list here. I've got Nancy and then I've got 13 Ada Sue on the list. 14 MS. SELWITZ: Mine was not on this topic. 15 DR. PRENTICE: All right. This stick with 16 this topic for a moment, then Susan and James -- I 17 think James, didn't you have your hand up first? 18 DR. POWELL: Yes, for another issue. 19 DR. PRENTICE: No, can't talk yet. All 20 right. Susan. 21 DR. WEINER: One of the major outcomes, 22 and obvious outcomes, potential outcomes of the use of 208 1 accreditation is to enhance public trust. And to 2 measure that, especially in the face of the recent -- 3 or not so recent events. And to answer that question, 4 I do think it's premature. But I think that it's an 5 important outcome on something that is not going to be 6 so easy to measure. 7 But to enhance public trust in the 8 research enterprise is something that we're all 9 committed to doing, and we want to make sure -- to do 10 that will also mean heightened awareness on the part 11 of the public about what accreditation -- not 12 accreditation but human research protection programs 13 are about. So it's likely to have outcomes like 14 clinical trial enrollment rates, stuff like that. 15 DR. PRENTICE: My feeling is it's 16 premature, Felix, at this point in time. Perhaps we 17 should have an opportunity to consult with AAHRPP and 18 ask them -- not necessarily to come here -- but ask 19 them to provide us some advice as to when do they 20 think it would be an appropriate time to pursue this 21 issue in terms of looking at with stuff, does it 22 really work; is it effective. Okay. 209 1 By that time, the CDC study will be 2 complete, and maybe it doesn't give you all the 3 information you want, but it will give you some 4 information about accreditation. So I guess that's my 5 feeling. Would you accept that and sort of table this 6 for a bit? 7 DR. GYI: I'm happy with that. 8 DR. PRENTICE: Okay. Nancy. 9 DR. JONES: I, too, looked up the charter 10 and one of the topics was investigator conflicts of 11 interest. And I don't know if I really want to tackle 12 that as much as just make an observation that SACHRP 13 has looked at human research protection from the 14 perspective regulatory burden for institutes, for IRB 15 member, for IRB managers, from a lot of different 16 perspectives. And we've even looked at human research 17 protection from the perspective of human subjects. 18 But one view that we really haven't 19 investigated or sought as much from their view of how 20 can we make human research protection better are the 21 investigators themselves. I know we've talked many 22 times about how these different new regulations -- 210 1 it's the investigator's responsibility. And in fact, 2 in Subpart A Committee, one of the committee members 3 wants us to look at the possibility of regulating what 4 investigators' responsibilities are. 5 But before we go down that track, I think 6 it would be informative for SACHRP to consider and 7 gather opinions or expert opinions about how do 8 investigators think human research protection could be 9 improved. What barriers do they experience in the 10 regulatory process towards protecting their subjects? 11 I think that that's an important perspective. 12 And we're often cognizant that these 13 regulations are understood only by the few, and not 14 necessarily the ones that are in the trenches trying 15 to protect human research interests. So I would 16 really like us to do some fact gathering, perhaps in 17 a panel initially. You could touch a little bit on 18 conflicts of interest, but I think that is only one 19 aspect of the advice that we could get from the ones 20 that ultimately are important protecting human 21 subjects. 22 DR. PRENTICE: Okay. Let me try to 211 1 understand where you're going. Obviously there are 2 thousands of investigators out there, and probably a 3 significant percentage of those thousands view the 4 hurdles and hoops they've got to go through as a 5 burden. Right. I mean, I think you would agree with 6 that. I don't know if that really speaks so much to 7 conflict of interest as it does to having to jump 8 through the hoops to get a protocol reviewed and 9 approved by an IRB. 10 So all you're saying that we ought to try 11 to find some representative investigators to come in 12 and address us and say, "Look, these are what our 13 problems are. We want you to know what they are." Is 14 that where you're going on this? 15 DR. JONES: I think that would be one 16 aspect of it. I think it's important to recognize 17 what the barriers are from the investigators. We've 18 focused a lot on the barriers that IRB regulators 19 have, what the burden is to them about AE events and 20 how they collect them and all these different things. 21 And we've focused on the perspective of what the 22 barriers are from institutions towards having a 212 1 central IRB and their liability issues. And I think 2 those are important parts of the process. 3 So I think it would be important as one 4 perspective to gain for the investigators what are 5 their barriers that they perceive in this process. 6 But that would only be one slice. I think it goes 7 beyond that. I think that there could be some 8 perspective gained from investigators about how do we 9 make this so that we can more effectively protect 10 human subjects. To not always look inside the 11 regulatory box, but to gain other -- to look a little 12 more broadly than just what are the barriers. 13 What are the ways -- and some of this 14 we've talked about in the perspective of how do you 15 communicate or educate people to use the regulations 16 so that they actually protect human subjects? We've 17 talked about all these different things, but it's 18 always been peripherally. 19 And every time I turn around, it's more -- 20 burden has been placed on the investigators, but we're 21 not really effectively capturing how do we enable the 22 investigators to carry this burden. 213 1 DR. PRENTICE: Well, I'll give you my 2 opinion. I've been doing this for a long time. I 3 think I know the perspective of many investigators. 4 I think I know what they think the barriers are. And 5 I know how I would address those barriers. It's a 6 function of resources. 7 If I had the resources available to me at 8 my medical center, I could help them develop informed 9 consent forms. They wouldn't have to do that. I 10 could have staff go out and help them to write their 11 IRB applications. They could do all sorts of things 12 for investigators to help them. We could go out and 13 go to individualized training to help them understand 14 the regulations. We don't have the resources at my 15 institution nor do most other institutions. 16 Consequently, what happens is the 17 investigator is left alone to try to cope with a 18 myriad of regulations that they don't always 19 understand. Okay. And the IRB doesn't always have 20 time to communicate appropriately with investigators 21 because they're overloaded and under-resourced. If 22 you look at the staffing of independent IRBs compared 214 1 with academic IRBs, you have Western with something 2 like 258 staff. They meet every day of the week or 3 twice a day. I don't know. They are able to provide 4 service to investigators that academic IRBs can't. 5 They develop consent forms for people. They amend the 6 consent forms. They translate the consent forms. 7 At my place, if we tell an investigator, 8 "Listen, we need a Hispanic consent form," we're not 9 going to do it for them. They've got to go out and 10 find the money and find the translator to go ahead and 11 do that and get it certified. At Chesapeake, I know 12 a lot about Chesapeake, they're also able to provide 13 many more services than we can. 14 So while I don't object to having 15 investigators come in and say, "Listen, these are our 16 problems." I suspect that all of us know what they 17 are. 18 DR. JONES: And then maybe to modify that 19 in terms of saying, "Let's address not just the 20 problem, but towards looking for the solutions." And 21 I'm not saying a gripe session. I'm not saying just 22 identify the problems, but actually what are effective 215 1 education means, what are effective resources, to make 2 an investigator -- I'm asking -- we have identified 3 the problems, and I agree that you have a good 4 perspective probably of what the problems are. 5 But it's never percolating to the point to 6 make all these regulations functional, in my opinion. 7 That we are coming up with new subparts, new composite 8 analysis that the investigators are going to be able 9 to identify what to put down on the paper to do it. 10 And what I'm saying is how do we enable that to 11 happen. 12 DR. PRENTICE: Education. Sensitivity. 13 Just hold on. We want to stick with this one topic, 14 right. Okay. Felix had his hand up first, then it's 15 Susan. Felix. 16 DR. GYI: I would be in agreement with 17 Nancy. You know, the Subpart A Subcommittee has been 18 charged by this committee to take a look at a range of 19 issues including perhaps new regulations for 20 investigators. And I think that intuitively we all 21 feel that there are regulations for groups that engage 22 in research but none for the investigators. 216 1 And so, before we go too far down that 2 path, it would be good for us to hear from the 3 investigator population. Here is my concern, though. 4 I mean, how do we sample that universe of 5 investigators appropriately? If we take a look at FDA 6 1572, in excess of 50, perhaps maybe 80 percent of 7 investigators who conduct a study don't come back and 8 do another study. 9 And so do we reach out to that particular 10 population and make sure that the regulations are in 11 harmony so that they all understand that? Because I 12 think that fundamentally, I do believe it's an issue 13 of education as opposed to gathering more data. 14 DR. PRENTICE: So how would you get a 15 representative sample of the tens of thousands of 16 investigators out there that could reflect the 17 investigator community at large? 18 DR. GYI: I understand that if you serve 19 lunch, most physicians will come. 20 DR. PRENTICE: We'd probably better move 21 hotels. Susan. 22 MS. KORNETSKY: I have a little bit of a 217 1 different slant on this, and I think Ernie, for many 2 years, up until this year, I sort of tended to feel 3 the same way, that it's a matter of resources and 4 education. But I've had the opportunity this year for 5 a couple of investigators who are very well educated 6 about IRB regulations and are very active clinical 7 investigators come up with some very creative ideas 8 and thoughts about ways of improving things. 9 So I think we have that on one side, but 10 I think there are a group that are sophisticated. And 11 when I think about what Nancy has suggested, I'm 12 thinking even outside of the box of what the 13 regulations are, if we're really looking at protecting 14 human subjects, what their ideas might be for 15 recommendations otherwise. 16 So I don't -- I think there's a lot of 17 investigators who will gripe and don't have the 18 education and would be very happy with resources; but 19 I have been amazed about some of our investigators who 20 are beginning to really be educated and come forward 21 now and say, "You know, there's a better way of doing 22 this. Or could we do it better?" So I don't want to 218 1 discount that, either. 2 DR. PRENTICE: Okay. Celia. 3 DR. FISHER: I just did want to remind the 4 committee that we did have such a panel. It was the 5 social science panel. We had four people who were 6 social science researchers come, and we might want to 7 reflect on what we ended up doing with that 8 information, which is basically nothing. 9 So as nice as the idea was/is, we 10 certainly have tried it and -- I'm a little kind of 11 pessimistic about -- for many of the reasons that 12 Ernie has listed, about whether or not we would really 13 use that. 14 DR. PRENTICE: Ada Sue. 15 MS. SELWITZ: Two comments. One, because 16 I wasn't on SACHRP at that point of when the social 17 science researchers came, but did you at any point 18 consider going to associations such as FASAB? I mean, 19 some of the existing associations that represent 20 researchers as individuals, not so much the COGRs and 21 the AAMCs that represent institutions, but some of 22 those, and ask for their feedback particularly in 219 1 terms of creative ideas. 2 I like that, and the positive side of 3 things is highest. I think all of us know the 4 perceptions of what the challenges are. But on the 5 other hand, there's something that's percolating and 6 I don't know whether it even belongs in Subpart A, but 7 the proposal that there should be regulations, a new 8 Subpart, on investigators. All right. 9 The focus on the regulations -- OHRP 45 10 CFR 46 should be expanded, maybe not in Subpart A. 11 That's why I'm not sure it belongs in Subpart A. But 12 there should be a new subpart or something to that 13 effect to regulate researchers similar or I guess 14 along the lines of what you find in FDA. 15 Now, I do not know what I think about that 16 suggestion. But assume that someone is worthy of 17 consideration. And this, in my mind, fits to some 18 degree in those considerations. I mean, you know, are 19 there creative things that can be done and suggestions 20 within the current system? Or do we in fact need to 21 actually be expanding the regulatory framework in 22 terms of 45 CFR 46? 220 1 DR. PRENTICE: You know, it's my 2 understanding that the Subpart A Subcommittee is going 3 to look at Gary Chadwick's recommendations sooner or 4 later; I don't know when. And I've looked at those. 5 It's an articulation of investigator 6 responsibilities that one would assume that any 7 investigator who conducts clinical research or any 8 kind of research in an appropriate ethical manner in 9 compliance with the regulations would subscribe to. 10 It's putting down on paper what they already do. 11 If they don't do it, then they should be 12 doing it. And if they're not doing it and they should 13 be doing it, then maybe it ought to be in regulations. 14 But that's a discussion that will occur at the Subpart 15 A Subcommittee. 16 So we're back to Celia, basically 17 indicated that we already had a panel and we haven't 18 done anything about it. Well, that's not totally 19 true. We hope that the Subpart A Subcommittee will 20 seriously consider the application of 45 CFR 46 to 21 Common Rule to behavioral social science research in 22 their deliberations. So I think that's going to come. 221 1 So do you think it would be worthwhile to 2 have a section of a future SACHRP meeting sometime in 3 the future, not necessarily the next one but maybe the 4 next one, devoted to investigators that would -- 5 DR. FISHER: Before you ask that question, 6 we have a lot -- you know, you're asking us to make a 7 decision about this, where there is a lot of other 8 ideas out on the table. 9 DR. PRENTICE: Actually we're not going to 10 ask you to make a decision. We're just asking you 11 what your feeling is. We're putting things on the 12 table for possible inclusion at a SACHRP meeting. 13 Now, if most of you say, "You know, it's not the 14 time." Or "Let's not do it." Or "It's not 15 productive." Then we need to get an idea that that's 16 the way you think. 17 On the other hand, if a lot of you say, 18 "Well, as Susan said, it's probably a good idea," then 19 we need to know that. 20 DR. FISHER: I am an investigator and I do 21 a lot of research and it all has to go before the IRB. 22 And I also advise other researchers who have 222 1 difficulties. My feeling about that is that some of 2 it is definitely ignorance and lack of education. But 3 I agree with Ernie, that the way the regulations are 4 currently written, what the IRB requires is ethical 5 behavior of investigators. 6 I'm not sure that -- and the monitoring 7 and the continuation of review and those kinds of 8 things is what is there to ensure that investigators 9 are doing what they should be doing with respect to 10 the regulations. 11 So I'm not sure -- first of all, at this 12 point, I would not see that there would be any 13 advantage to having separate rules for investigators. 14 But also, I'm really concerned about the 15 representativeness of any particular panel in terms of 16 an investigator. An investigator that speaks to Susan 17 is probably so exceptionally well versed in 18 regulations that -- they all are -- that the extent to 19 which they represent that universe of investigators 20 that are really out there. 21 And then I think the other side of it is 22 that the universe of investigators that are out there 223 1 don't understand the regs. And so it -- we always get 2 into that particular kind of conundrum. 3 So although I think -- and I think this 4 was our notion with the social behavioral, and I'm not 5 saying that we ignore them; I'm just saying that the 6 recommendations, the specific recommendations that 7 individual investigators made are not doable within 8 the structure of where we are, or they are issues that 9 we are already kind of grappling with. So I'm just 10 not sure in terms of the committee's time where -- how 11 productive another panel would be. That's just my 12 opinion. 13 DR. PRENTICE: Susan. 14 MS. KORNETSKY: I can understand what 15 Celia is saying, and I guess I'm looking at it a 16 little differently. I usually don't disagree with 17 Celia; I don't like to do that. I just want to say I 18 think the behavioral social science panel as 19 investigators has additional issues than just being an 20 investigator. And I think a lot of that came through 21 just the issue of doing behavioral and social science 22 research in more of a bio-medical sort of model. So 224 1 I think there was stuff that came along with that. 2 I guess, and maybe it's not a good use of 3 the committee's time, I guess my sense is not that any 4 one, two or three investigators would represent 5 investigators, because I don't think you can. I think 6 Celia is right. But I think there probably are, and 7 I think probably if you looked around the room and 8 spoke to some of us, there probably are some people 9 who are very thoughtful and knowledgeable about this 10 that could just throw out some ideas, even if it is to 11 help prioritize. 12 Even if it's not to be responsive, but so 13 that we say, "This really is an issue. This is really 14 an issue for the investigator community." And I think 15 it should not be a gripe session. You would have to 16 be very careful about the people that you chose. 17 These would have to be well-seasoned, 18 educated investigators who have experience with the 19 system, and in some respects, respect for the system. 20 But to really ask them to be creative in helping us 21 think through some of the issues. So I'm looking at 22 it maybe a little bit differently, more advisory, to 225 1 help us think through priorities. 2 DR. PRENTICE: Okay. Any other comments? 3 James, you had your -- you probably forgot what you 4 were going to ask. 5 DR. POWELL: Just about. But what I 6 wanted to bring to the table was an issue that I have 7 been working on for a number of years. It relates to 8 diversity in the clinical research process. And when 9 some of you may know that FDA issued this guideline in 10 September on collection and documentation of ethnicity 11 and race in clinical trials, this final guideline. 12 But it doesn't -- there's no requirement 13 in FDA regulations that there be inclusion of ethnic 14 and racial minorities in clinical research, as far as 15 I'm aware, whereas in NIH research, there is a 16 requirement that there's a strategy for appropriate 17 inclusion of ethnic and racial minorities in clinical 18 trials. 19 And one of the issues that I've had is 20 that oftentimes trials of new medications are 21 available without data showing their safety and 22 effectiveness in certain segments of the population. 226 1 So I would -- the NIH has been successful in gathering 2 data in ethnic and racial minorities, and they do 3 report out I believe on an annual basis data on 4 inclusion, gender and ethnic and racial inclusion. 5 I would like to see that the committee 6 consider whether or not it would be appropriate to 7 harmonize the guidelines in between NIH and FDA with 8 respect to inclusion of ethnic and racial minorities. 9 DR. PRENTICE: Dr. Lepay, you know I would 10 ask you to respond. 11 DR. LEPAY: Well, I do appreciate the 12 reference to our guidance on looking at ethnic groups 13 in clinical trials. You're correct on one end, and I 14 probably need to explain another. Yes, indeed. 15 Inclusion criteria, at least requirements 16 as far as inclusion in clinical trial, are not so 17 specific relative to FDA regulated clinical trials. 18 On the other hand, there are specific requirements in 19 regulations about how studies have to be analyzed, and 20 that includes provision for analyzing by gender and by 21 ethnicity. 22 And at some level, we also certainly have 227 1 regulations as we're getting information or as we're 2 getting data in from outside of the United States that 3 do also require the studies that we accept for 4 purposes of FDA review have to represent a population 5 that would exist in the United States in order for the 6 study to serve as a sole basis for approval. 7 So in essence, I think there are certainly 8 areas that we need to further discuss, we need to 9 further consider. Part of this is also looking at not 10 only what we can put into regulations, but what 11 support we have with any kind of regulatory process, 12 for what our legal authority is to be able to 13 promulgate regulations. 14 We all know that there are certain 15 differences in terms of the laws that govern the 16 funding of research versus the laws that govern 17 research coming in for purposes of FDA decision 18 making, which is a bit different and a different level 19 of control. 20 But I think certainly this is an important 21 area that deserves attention and deserves further 22 discussion. I'm not sure that we can actually make 228 1 quite the comparisons that you might suggest between 2 NIH again and FDA because of these differences between 3 funding authority and regulatory authority. But I 4 think it is a very important area that needs to be 5 addressed. 6 DR. PRENTICE: Is this something that is 7 or going to be addressed by FDA, or is it something 8 you think SACHRP should be involved in? 9 DR. LEPAY: Again, it's very difficult for 10 me to say exactly how SACHRP fits in or how SACHRP 11 can fit into these areas. Obviously that's something 12 that SACHRP needs to work through in terms of its own 13 agenda setting and how it can relate to the PHS 14 regulations and what kind of recommendations we can 15 build from those PHS regulations. 16 DR. PRENTICE: Okay. Ada Sue, then Celia. 17 MS. SELWITZ: First let me make sure, do 18 you want to talk about this topic? I'll let her talk 19 about this topic. 20 DR. PRENTICE: Okay. 21 DR. FISHER: I think if it's in our 22 purview, an issue about harmonization in terms of 229 1 diversity in the types of research, is critically 2 important. I think analyzing data after the fact is 3 really not good clinical science practice because 4 you're left with irregular Ns; you haven't identified 5 in advance the specific population characteristics 6 that would be necessary to get the appropriate 7 representation. 8 And I think it's critically important to 9 correct ethnic and racial disparities in this country 10 to have from the outset the attention to diversity 11 rather than simply as an end process, and "Oh, that 12 looks like -- this small pocket looks maybe they're 13 behaving differently, or maybe they're behaving the 14 same." 15 So I think it's critical for public health 16 that we examine that issue of harmonization if in fact 17 that's something that SACHRP can do. 18 DR. LEPAY: I may need to respond again, 19 just again for clarification purposes. I don't mean 20 to imply by any means that in protocol development and 21 protocol design as it goes on in negotiations and 22 discussions between sponsors and FDA that these are 230 1 not issues that are discussed, and that these are not 2 issues that are built into clinical trial protocols. 3 I think what we're talking here is what 4 the regulations can actually say and require and build 5 in. And you have to watch, again, how specifically 6 you can write regulations. I mean, one tries to write 7 the regulations to reflect justice; but I don't know 8 that you can say in a regulation that this proportion 9 of subjects has to be from this group and this 10 proportion of subjects has to be from this group and 11 so forth. 12 So we have to be careful, in fact, of what 13 we can put in regulation, what is already perhaps in 14 guidance in specific areas, and what are some broad 15 recommendations we would have. Which I think is what 16 SACHRP can perhaps best embrace. 17 DR. POWELL: And one of the things that we 18 have talked about, and Dave, you have talked with FDA 19 as you know about this before, is that it should at 20 least represent the patients have the disease, at 21 least proportionate with -- if there's an excess 22 burden of a particular population and a disease, then 231 1 certainly the clinical trials and the processes for 2 understanding therapeutics in that area should take 3 into the account what part of the population actually 4 has the disease. 5 DR. PRENTICE: Okay. Yes. 6 MS. SELWITZ: And again, I know we're 7 running out of time. I think this is interesting that 8 we're talking about future priorities, which I think 9 are important, but I think we have a lot of priorities 10 that are still on our plate. And I think a number of 11 those are with Subpart A. 12 And quite frankly, when Susan said that 13 the charter ended in October 2006, if you all had any 14 other response beyond the one you did, I'd have to be 15 saying, "OHRP, could we afford to set up a second 16 Subpart A Committee so that we could move more 17 quickly?" And I'm quite serious about that, because 18 I think everything that has been mentioned is 19 terrifically important and would be of tremendous 20 value. And I've been interested in everything. And 21 I would like to talk about -- I had questions. 22 I don't know if we're going to have time 232 1 for international and also the evidence-based. I 2 mean, I thought both of those this morning were 3 interesting. I'd like to get a better handle on 4 evidence-based, and I wanted to hear Joan and I 5 noticed that Peg left, but what -- I thought Ernie 6 asked the question to you all that I would've like to 7 have known is -- I would like to see us do something 8 in international, but I don't know how to get my hands 9 around it. 10 And I wondered if you all had thought 11 about it and had. And I notice you're noticing -- 12 you're nodding yes, so we still, if we have time, I 13 would like to hear that. But notwithstanding that, we 14 do have -- there's a lot on the plate now that is in 15 Subpart A. I mean, I think Subpart A needs more like 16 eight years rather than -- and I'm not -- that has 17 nothing to do with how fast any group can move, but 18 it's certainly important. 19 If we have a chance at this point, I would 20 like to talk a little bit about international and 21 evidence-based, and I would like to know if Joan and 22 Peg discussed at all in the interim what would be 233 1 other options. Or how you think SACHRP could get 2 their hands around the international issues. 3 DR. PRENTICE: Okay. They did, and we do 4 need to consider international research and evidence- 5 based programs. But before we embark on that, I'd 6 like Bern to make a comment on renewal of the charter. 7 DR. SCHWETZ: We have gotten no indication 8 that there is a possibility or a likelihood that 9 SACHRP would not be re-chartered in a continuous 10 process. We went through this two years ago as well. 11 And I would encourage you to make plans for the future 12 with the assumption that SACHRP will continue, not 13 that it will stop. 14 MS. SELWITZ: So you're saying we can't 15 have two Subpart A Subcommittees? 16 DR. GYI: We would be delighted to have 17 six. If I could just follow on the principle that Dr. 18 Fisher had raised before. Now, the international 19 research had been addressed when Dr. Lane Boland (ph) 20 was here one time as well. And I think it would be 21 worthwhile for us to hear some of that transcript, 22 because I don't remember all the details. But 234 1 certainly we ought not to be spending a lot of time 2 reinventing the wheel every time we decide that that's 3 an important topic. 4 DR. PRENTICE: Okay. It's 2:53. We're 5 technically supposed to have a break at 3:00, but I 6 know some people have to leave. Remind me again when 7 your flights are. Okay. Thank you for that. Yours 8 at 2:30; you've already missed it. When are yours? 9 Not a problem with you. 10 MS. SELWITZ: I'll stay as late as you 11 want. 12 DR. PRENTICE: All right. My flight is 13 7:45, Sue, so how about 7:00? Yours at 6:00, I know 14 that. Would you entertain continuing without a break? 15 All right. Let's do that. 16 In consideration of the fact that our ex 17 officios have spent a lot of time talking about their 18 priorities and so far their priorities have not been 19 raised except by -- we've not really addressed their 20 priorities, so I think we really need to do that. And 21 I would like to invite Joan -- I guess Peg's not here 22 -- Joan to come up. 235 1 And if you recall, at some point during my 2 opportunity to ask questions I said, "You know, what 3 do you think we can do? What should we do?" You 4 don't have to stand. If you want to go over there and 5 sit down, you can. 6 MS. PORTER: Peg did have to leave 7 unfortunately, but I wanted to tell you that we did 8 discuss Ernie's question at lunch between ourselves 9 and with others. And basically we're thinking that 10 where the first panel left off was not such a bad 11 place to start. 12 They emphasized the need to understand and 13 agree upon what our equivalent protections, and also 14 to look at the FWA mechanism and how it is currently 15 constructed, whether or not it works, how useful it 16 is, and the desirability of having other federal 17 departments and agencies use a similar kind of 18 mechanism; if not that one itself, at least something 19 like the FWA in an international context. And how it 20 can be so constructed that it does not foster any 21 implications of imperialism. 22 The second area is training, both for 236 1 foreign IRBs which the first panel did look at in some 2 depth in looking at infrastructure; for U.S. IRBs and 3 for U.S. researchers. Then we thought a greater 4 discussion of how we achieve understanding of the 5 local context would be helpful. How do we understand 6 the local context so as to offset any coercion, 7 address vulnerabilities in country, and appreciate 8 community involvement? 9 Appropriate oversight is another area. 10 FWAs are used by HHS. That's one mechanism of 11 oversight; are there others? And then the question of 12 clearances by the Department of State. Do we need to 13 do that more systematically within HHS and across the 14 federal sector? 15 So those are our priorities that we came 16 up with. And depending on which questions you would 17 want to pick to hone in on, I think the mechanism 18 might vary. Certainly it could be done through a 19 subcommittee structure of SACHRP, probably working in 20 conjunction or with a lot of liaison from the 21 International Working Group of the Human Subjects 22 Research Subcommittee. 237 1 Or it could be if we have the questions 2 well enough framed could be sent to individual groups 3 for consideration outside of the SACHRP and HHRS and 4 OHRP membership. So that's where we're coming down as 5 our highest priorities, and really again, that's about 6 where the last panel left off in selecting high 7 priorities for consideration themselves. 8 Another option that we came up with is 9 another Subpart A consideration, because as you know, 10 Section 101(h) under the Common Rule deals with the 11 possibility of establishing what is at least 12 equivalent in international settings. So that's a 13 regulatory measure already contained in Subpart A. 14 And certainly in Section 103, assurances, 15 what is a satisfactory assurance in an international 16 context. So Subpart A could theoretically embrace 17 some of these basic questions as well, although 18 Subpart A is pretty busy. 19 So that's what we came up with over lunch. 20 I guess the first priority would be -- first option 21 would really be another subcommittee to hone in on 22 some of the regulatory issues, Ernie. 238 1 DR. PRENTICE: Okay. Joan, thank you. 2 I'd like to seek your advice. And let's take one of 3 two of your priorities, and you can address either 4 one; it doesn't make any difference. I just want to 5 get your feeling about how a subcommittee would 6 approach pursuing that particular priority, because 7 I'm unclear. 8 Let's take what are equivalent 9 protections. You mentioned the international 10 compilation of human subject research protections. 11 They're there. There's a bit of a comparison. You 12 know that Barbara Mishkin has also done a comparison. 13 We know that different countries subscribe to 14 different guidelines. What would you envision a 15 subcommittee doing in terms of addressing this issue 16 of what are equivalent protections? That would be one 17 thing you could address. 18 Or training. What would a subcommittee do 19 in terms of looking at training for foreign IRBs, for 20 IRBs in the U.S. who review projects conducted 21 overseas as well as investigators who conduct projects 22 overseas? What do you see a subcommittee doing? 239 1 MS. PORTER: With regard to the at least 2 equivalent protections, this undergirds everything, 3 and I don't think we're going to get a harmonization 4 amongst federal departments and agencies; I don't 5 think we're going to get at a really clear FWA 6 international assurance until we have that. 7 I would see a -- and I know that there are 8 other efforts going on to try to come to some 9 consensus on what is at least equivalent, and those 10 have gotten pretty far along the way. But I think 11 that a subcommittee of SACHRP could look at what see 12 in 45 CFR 46 and Subpart A and perhaps in the other 13 Subparts that could be gleaned out to say, "These are 14 the minimal things that we would accept and expect an 15 international institution to follow and to be followed 16 by U.S. researchers and U.S. IRBs when that kind of 17 research is carried out." 18 So I think some good thinking and 19 deliberations and our own recommendations as to what 20 must be necessary when there's an agreement to fulfill 21 the criterion of at least equivalent. So that to me 22 would be an activity that could be fleshed out in the 240 1 subcommittee forum. 2 As far as training for foreign IRBs, 3 again, I think the first panel addressed that in some 4 depth with infrastructure building. I think it would 5 be good for us to try to do a survey or gather more 6 information about what actually is done now at U.S. 7 institutions that carry out a great deal of 8 international research and see if we can glean from 9 that what their practices are for training 10 investigators and for helping their IRBs establish 11 procedures to learn about local context, is to really 12 use that manpower to find out more systematically what 13 is going on currently. 14 DR. PRENTICE: Okay. You had your hand up 15 first. 16 DR. CARR: Hi. I'm Sarah Carr. I didn't 17 introduce myself before. I'm sitting in for Amy 18 Patterson at NIH. And I just have a question about -- 19 maybe for OHRP about the -- I think in the spring, 20 OHRPs went out for public comment on a proposal of a 21 working group for some criteria about equivalent 22 protections. 241 1 And I wonder what the status of that is, 2 and whether a subcommittee of SACHRP might pick up on 3 where that effort is, or whether any activity of 4 SACHRP ought to wait for further development in OHRP 5 on that guidance. 6 DR. SCHWETZ: The comments were received, 7 and OHRP is in the process of looking at that comments 8 and trying to figure out how to adjust the document in 9 response to the comments that were received. 10 And at this point, if the next question 11 is, when will be done, it isn't clear, because this 12 isn't an absolute highest priority for OHRP. And we 13 don't have other federal agencies telling us it's a 14 real high priority for them for us to get this done, 15 so we're working on it in the context of other 16 priorities. 17 MS. PORTER: Could a subcommittee of 18 SACHRP be helpful in moving that process along to 19 develop a consensus or a model for at least 20 equivalent? For VA, it really is quite a high 21 priority, actually. 22 DR. SCHWETZ: It isn't clear to me that a 242 1 working group or a subcommittee of SACHRP could help 2 because as the federal agency that's responsible for 3 responding to the comments, we have to do that, and we 4 can't delegate that to somebody else. 5 Now, if somebody else picked up after 6 we're done with it and drew some conclusions, wanted 7 to make some recommendations, it's possible that 8 SACHRP could get engaged at that time. 9 MS. SELWITZ: My question was the same as 10 actually. I wanted to know -- I do agree, Joan, the 11 equivalency and having guidance in that area is 12 critically important. And I just wanted to know where 13 you all were and when you thought something would be 14 coming out. 15 DR. PRENTICE: Felix. 16 DR. GYI: And along those lines, I think 17 that if we had to choose between looking at 18 equivalency and at least looking at some standards 19 that might be acceptable through OHRP, that that's 20 something that I would endorse. But it sounds like 21 there's already a process in place, and rather than 22 have redundant efforts on a parallel track, I wonder 243 1 if we might want to wait until we hear from OHRP 2 regarding what the status of their findings are. 3 DR. SCHWETZ: Ernie, if I might clarify 4 with Irene and Glenn and others who would refresh my 5 memory. The equivalent protection document that's out 6 there is not the dictionary of equivalent protections. 7 It's guidance on how to evaluate whether or not 8 protections are equivalent. But it isn't a step-by- 9 step analysis that gives you a yes or no answer with 10 every question that you put to the document. 11 So if, in fact, that's what's needed, 12 you're going to be disappointed when this document is 13 finally put out there, because it is only going to 14 give you guidance on how to answer that question, but 15 it isn't going to give you the answers. 16 DR. GYI: Dr. Porter, does that meet your 17 needs, I mean, in terms of what the VA would be doing? 18 MS. PORTER: Well, we're awaiting the 19 guidance on how to effect the process, but 101(h) 20 allows the department or agency head to declare what 21 is at least equivalent, in terms of international -- 22 with the Common Rule expectations. And so we have -- 244 1 and no one has really invoked 101(h) except for 2 perhaps one federal department. 3 So we have the possibility of having 4 multiple federal departments come up with different 5 ideas of what is at least equivalent, or even coming 6 up with a case-by-case basis of what is at least 7 equivalent. 8 So I think from the standpoint of the 9 International Working Group, we would find it very 10 helpful if there were some consensus on what we could 11 declare at least equivalent. Is it just having an 12 informed consent process? Or is it having an informed 13 consent process with all of the elements? Is it 14 having an IRB, or is it having an IRB with just five 15 members? And exact requirements in 45 CFR 46. So 16 where do we draw the line for equivalency? 17 I think that across the whole federal 18 sector if each department and agency is deciding 19 somewhat differently, we have a potential for a lot of 20 disharmonization, if you will, in our interactions 21 with other countries and with other foreign 22 institutions. 245 1 DR. GYI: I'd just like to share with you 2 that I agree with you, having been involved on those 3 levels. I do see the countries interacting with us to 4 be confused with respect to how we might interpret 5 what are equivalent protections. And things like 6 informed consent, documentation of informed consent, 7 and the elements of informed consent continue to 8 plague the research community there as well. 9 So it would be helpful for us to have some 10 guidance that would be a little bit more substantive 11 and meaningful. So if there is a way for us to move 12 in that direction, I would be supportive of that. 13 MS. PORTER: Would it be appropriate to 14 call on other members of the International Working 15 Group to give their comments as well on what they've 16 seen? 17 DR. PRENTICE: I am looking at the October 18 1, 2005 International Compilation of Human Subject 19 Research Protections. It's the second edition. It 20 expands the list to encompass 72 countries. It's a 21 compilation of laws, regulations, guidelines 22 pertaining to human subject research that was able to 246 1 be identified. It was put together by OHRP. It's not 2 -- it does not imply that these were equivalent. 3 It is more or less a listing of these 4 regulations and guidelines. And in some cases, you've 5 got multiple guidelines and regulations; in other 6 cases, you don't. Some of them pertain to drugs; in 7 other cases, they don't. As far as I know, OHRP at 8 the moment has, what, four or five that you accept as 9 equivalent. Is that correct? How many? Five. 10 Okay. So clearly you're not talking about 11 -- 12 MS. STITH-COLEMAN: I would just caution 13 that these are guidelines that the presumption is in 14 addition to these guidelines, there are other parts of 15 Subpart A that is also part of the terms of assurance. 16 So just want to clarify that. And I believe there are 17 five of those codes. 18 DR. PRENTICE: Okay. Joan, what you're 19 telling me is that not all federal agencies are on the 20 same page relative to this? 21 MS. PORTER: That's correct. 22 DR. PRENTICE: Well, is this not a problem 247 1 for the federal government to resolve as opposed to 2 SACHRP? I mean, it seems to me that if different 3 federal agencies are applying different requirements 4 and they're supposed to all be applying the same 5 requirement if they're subject to the Common Rule, 6 right. I would assume the discussion is taking place 7 among these agencies to try to harmonize this. So I'm 8 a little bit unclear as to how SACHRP could help do 9 that. 10 MS. PORTER: Well, I think in terms of 11 identifying -- I guess I'm going to ask Irene and 12 others if the federal-wide assurance is a declaration 13 of at least equivalent in the international setting, 14 because is the sum total of the codes that are 15 recognized in the international setting in the FWA 16 plus the other terms of the assurance; would you 17 really consider that to be at least equivalent? 18 MS. STITH-COLEMAN: We consider the codes 19 in addition to the additional parts, Subpart A, B and 20 C and D as being equivalent. So basically, you know, 21 equivalency for us is equivalent to 45 CFR 46 and all 22 of the Subparts. 248 1 MS. PORTER: That is your declaration of 2 equivalency? 3 MS. STITH-COLEMAN: Yes. 4 MS. PORTER: Okay. 5 DR. SCHWETZ: Let me just try to fill the 6 other half of that thought, which means that if the 7 other regulations or guidances or whatever other 8 countries have put together, if they don't cover 9 what's in our regulation, it's not equivalent. Isn't 10 that correct? So in that sense, where there is 11 duplication and it's the same as 45 CFR, they're 12 equivalent. But if other regulations don't cover 13 those parts, they're not considered equivalent, if 14 there's only one side of it. So there will be holes 15 in the regulations. 16 MS. STITH-COLEMAN: At this point. OHRP 17 has not made any determination of equivalency. So we 18 at this point have not made any, and it would require 19 a Federal Register Notice, similar to what I think you 20 made reference to, Joan, and we have not yet done 21 that. 22 MS. PORTER: So inasmuch as HHS hasn't 249 1 perhaps agreed on exactly what would be at least 2 equivalent and others are looking to SACHRP to follow 3 the lead, I guess I'd say -- encourage SACHRP to look 4 at it on behalf of HHS with a goal of helping the 5 other departments and agencies as well in terms of 6 their interpretation. 7 And in addition to really evaluating the 8 federal-wide assurance in the international context to 9 see if it's working, if it's a good idea, what 10 advantages it really has in terms of protecting 11 subjects abroad. 12 DR. PRENTICE: Okay. Let's pursue that 13 one. If you conduct federally funded research, you've 14 got to have FWA; it doesn't matter whether it's 15 domestic or foreign, right? So the FWA is a document 16 where the institution more or less promises to follow 17 the Common Rule and the Belmount Report or whatever 18 else is in a FWA. And that's what they do. 19 There's no guarantee that any institution 20 in the U.S. or abroad is going to follow that simply 21 because someone signs that document. I mean, clearly 22 we've had significant incidents of non-compliance in 250 1 this country that resulted in shutdowns and all these 2 people signed, and PAs back in those days. So you say 3 does it work. 4 Well, I don't know if it works or not. I 5 suspect in some cases it works; in some cases, it 6 doesn't work. How do we get at how does it work, when 7 does it work, and when doesn't it work? We can't even 8 find out that information in the U.S. How do we do 9 that abroad? Joan. 10 MS. PORTER: I can't answer that question. 11 I'm looking for help to see how we do it, but I do 12 think it's important that we formulate a plan to try 13 to assess the effectiveness of it because it's a major 14 facet of our protections program. 15 DR. PRENTICE: I mean, one thing that 16 accreditation does, and certainly there's initiative 17 by AAHRPP to accredit foreign HRPPs as they go over 18 there. And they do -- the institution has to do a 19 self-study and then there's a site visit where it's 20 evaluated as to whether or not they're in compliance 21 with "the Common Rule." 22 Short of something like that, I don't know 251 1 how you'd get at that data. Or am I missing 2 something? 3 DR. HOLTZMAN: Well, I just wanted to say, 4 I mean, I think what we have to do is carefully 5 evaluate our own programs first to see what we're 6 doing in the international arena because as part of 7 this committee, it was the first time that I had 8 really looked into our international research 9 portfolio, which isn't that large. 10 I was surprised to find out compared to 11 some of the other agencies. But I've just started now 12 to see what we're doing and I think we -- your idea of 13 a survey, I think we need to do that really in-depth 14 to see what we're doing and what we can find out about 15 our international partners. And then maybe beyond 16 that, accreditation. That's another avenue we can use 17 to do that. 18 DR. PRENTICE: So would it be appropriate 19 for all federal agencies that sponsor research 20 overseas to try to find out what goes on over there in 21 terms of some sort of a survey mechanism as you're 22 apparently doing, and maybe some other agencies are 252 1 doing? 2 DR. HOLTZMAN: I think so. I mean, this 3 was just something we talked about, the International 4 Working Group Subcommittee talked about surveying each 5 of our agencies. And I think we need to probably do 6 that more in-depth than what we initially did. 7 DR. PRENTICE: Ada Sue. 8 MS. SELWITZ: This morning, one of the 9 things I thought I wanted to ask and then I got the 10 impression that there simply wasn't an answer to it, 11 so I wanted to ask: well, does each agency know how 12 much and what percent of their resources toward 13 research, involving human subjects occur 14 internationally? 15 And I'd really be interested in that, but 16 I got the impression that that data -- those datas are 17 not available. It might be in some agencies and not 18 at others. And I don't know if -- Sarah, I had an 19 impression that NIH it's not available. Is that -- 20 DR. CARR: Actually, I think we certainly 21 know how many foreign awards we're making. It's a 22 little harder to tell how many those relate to human 253 1 subjects research. That's a harder number to come up 2 with, I think. But actually, we are a participant in 3 the HSRS Subcommittee on international research and -- 4 actually, we have two staff who are participating in 5 that and they did make a presentation, and I wish I 6 had that data handy to relay to you. But I think NIH 7 does have a pretty good handle on this. 8 And I'll also say that NIH as part of our 9 extramural research program is looking at 10 international issues and foreign awards and the 11 management and oversight of those awards. And this 12 group has four subcommittees, one of which is an 13 ethics subcommittee looking at some of the ethical 14 issues and challenges. 15 And if there's any -- as you think further 16 about what, if anything, you want to do in this arena, 17 maybe it would be worthwhile to before you go forward 18 in any way, if you do, to hear more from the staff who 19 are involved at NIH in analyzing some of the data on 20 foreign awards. 21 And this group actually did confer with 22 other agencies last year, as well. And I think they 254 1 tried to identify best practices for the oversight of 2 awards. And so I'm sure they would be more than happy 3 to report to you, if that would be worthwhile. 4 MS. PORTER: We asked each of our federal 5 department and agency representatives in their 6 presentations to give us an idea of the magnitude of 7 the international research effort. And NIH did have 8 a pretty good handle on it in terms of numbers of 9 projects, countries. But even those data were not 10 pure because sometimes there's a multi-site award and 11 it's difficult to tease out what part of that award is 12 in a foreign component versus what's in a domestic 13 component. 14 But I must say we were all blow away by 15 the high figures and the high numbers. We had no idea 16 that there was much international research going on. 17 The other departments and agencies 18 probably have less of a handle on it. They simply do 19 not keep the data in a central location on what is 20 going on in international research. And there's very 21 little oversight and understanding of what is being 22 carried out. 255 1 MS. SELWITZ: So are you suggesting then 2 a SACHRP role would be to make recommendations that 3 this kind of data should be collected in DNA? I'm 4 very interested in international and I'm all for 5 subcommittees, if I can figure out what that 6 subcommittee would do within the context of what 7 SACHRP is supposed to, and in light of all the other 8 things that need to be done. But is that the kind of 9 thing you're thinking of? 10 MS. PORTER: Well, it might be 11 appropriate, as Sarah suggested, to have an idea of 12 what their committees are working on. And our report 13 will be due early -- it's due early this January. So 14 we will have completed the discussions with all of the 15 federal department and agency representatives by that 16 time, and we will have compiled data in key areas 17 about number of projects, vying of projects, nature of 18 the research going on, whether there's a central 19 office responsible for international research in each 20 one of the departments and agencies, whether an 21 assurance mechanism is used, what they see as 22 principal barriers and concerns. 256 1 So we will have more data at some later 2 point, so it's possible that we could revisit this 3 issue when our report is pulled together a little more 4 directly. At this point, we're only able to offer you 5 what we see as some of the major concerns and 6 constraints in understanding subjects and looking 7 toward HHS, looking toward knowledgeable good thinking 8 bodies to help us out with some of these really tough 9 pervasive issues. 10 MS. SELWITZ: I might add, you know, from 11 a slightly different perspective because you're 12 thinking about it in terms of research in which 13 they're being funded and run by investigators that are 14 outside of this country. You know, those of us that 15 are domestically, struggle with the review of 16 protocols that are being run by own investigators in 17 international settings. 18 And how -- that's why I've been interested 19 in what OHRP was going to come out with on equivalent, 20 from a different perspective. But I think it's very 21 important, because we struggle in this country on how 22 do apply it, how do we ethically do it, how do we get 257 1 local input. And I think those are important issues 2 as well in the international arena. 3 DR. JONES: And just to follow that 4 comment, if you could actually collect your data in 5 that way, it would be informative. Which ones are the 6 -- the foreign investigator is the PI, and the 7 responsible IRB is an international IRB, versus which 8 ones are collaborative between maybe and have dual 9 oversight versus which ones are American initiated 10 investigations and the American IRB is the IRB of 11 record? 12 DR. PRENTICE: Okay. Before I make a 13 comment, I want to ask James a question. You think 14 that PhRMA has any data on clinical trials placed 15 overseas by country? 16 DR. POWELL: I don't believe there is a 17 central place that has that data because I would 18 expect most countries typically hold that kind of 19 information fairly close. So I know that there are a 20 lot of efforts right now to try to of course catalog 21 what trials are going on and what each company is 22 doing, but I don't think there's such a database that 258 1 would include all of the trials that a company is 2 executing in different parts of the world. 3 DR. PRENTICE: Okay. Do you think that 4 some of the major pharmaceutical firms would be in any 5 way receptive to coming to SACHRP and telling us about 6 their clinical trials placed overseas? Or would they 7 consider that to be confidential and really don't want 8 to get into any discussions? 9 DR. POWELL: I think you would be able to 10 get some people from different companies to come in 11 and talk about that. I think that would be a good 12 exercise. 13 DR. PRENTICE: Okay. It seems to me that 14 in looking at the list of your priorities, Joan, and 15 you went through a number of very important issues -- 16 you know, what are equivalent protections? Does the 17 FWA work? What about training? What about 18 understanding the local culture, the local context? 19 Oversight and clearance by state departments, I guess. 20 But in considering all those priorities in 21 the follow-up discussion, we don't seem to have a lot 22 of data. You said that. Nobody seems to know what's 259 1 going on. Some agencies, NIH has more perhaps than 2 others. Maybe what we need to try to do here is 3 before we start looking at things like equivalent 4 protections, let's find out what's going on overseas. 5 I don't know personally. 6 All I know is there's a tremendous 7 migration of clinical research overseas. I have no 8 idea how much is funded by the federal government 9 versus pharmaceutical industry. Maybe we could think 10 about having a panel where that data would be 11 presented. At least that's a start. 12 What do you think? I mean, you've thought 13 about this a lot more than I have. 14 MS. PORTER: I think that would be 15 helpful, Ernie, to get as much information as we can. 16 I must say that the way the data are kept in the 17 federal departments and agencies doesn't give us a 18 real -- to use someone else's term this morning -- 19 real low hanging fruit on what we can find out about 20 what's going on. 21 We're trying to do this systematically as 22 much as possible but hit a lot of barriers and just 260 1 lack of compilation and lack of understanding of 2 what's going on. So inasmuch as we can get 3 information from any sources that would help us throw 4 light on some of these significant priorities, I think 5 that would be useful. 6 DR. PRENTICE: Is your subcommittee or 7 your working group within the subcommittee trying to 8 get a handle on all of the agency involvement? Is 9 that what you're trying to do? 10 MS. PORTER: Yes. We're trying to 11 systematically approach each federal department and 12 agency that is a member of the Human Subjects Research 13 Subcommittee to ask for presentation on some of those 14 areas that I suggested. And that's nature of their 15 international research, their roles in overseeing it 16 or regulating it, what their policies and procedures 17 are to this, what their organizational structure is 18 like regarding overseeing international research, a 19 variety of questions like that. 20 Whether they use the assurance mechanism, 21 or if they don't use that, what do they use. We want 22 to know how they're monitoring. Whether they require 261 1 local institutional review boards. How they're 2 institutional review boards in in-country, here in the 3 U.S., communicate with those that have been 4 established in an international setting. So there's 5 a whole great deal of information we've been trying to 6 collect here, and some of it is quite spotty. 7 DR. PRENTICE: And when did you say you 8 might be able to complete this task? 9 MS. PORTER: We're hoping to complete our 10 report about early January. I think we're shooting 11 for that. Right. And we'd still like a little time 12 for our HSRS participants to digest it, understand it, 13 massage some of the data, see where they think some of 14 the concerns rise to the top. But it is going to be 15 done and fairly soon. And I think we would be 16 delighted to share what we have found with SACHRP once 17 that's completed, if the HSRS agrees. 18 DR. PRENTICE: Well, it would seem to me 19 that SACHRP needs more data, more information, before 20 we can determine what we should, if anything, you 21 know, embark upon. And it might be ideal to have that 22 report presented to SACHRP at an appropriate meeting, 262 1 perhaps involve the pharmaceutical industry as well to 2 find out what's going on. 3 You know, we have three meetings next 4 year, and there is no agenda set for the three 5 meetings except for the Subpart A and the Children's 6 Research Subcommittee to present their ongoing work. 7 So perhaps that would be a possibility for a future 8 SACHRP meeting, unless I hear any objections to the 9 contrary. What do you think? Don't everybody speak 10 up at once. 11 DR. GYI: I like the idea. 12 DR. PRENTICE: You like the idea? 13 DR. GYI: Yes. 14 DR. PRENTICE: Okay. Good. All right. 15 MS. PORTER: Okay. Thank you. 16 DR. PRENTICE: Now, we've not had an 17 opportunity to talk about evidence-based projects that 18 Sally talked about. First of all, Sally, I think that 19 this is important. I think this kind of dovetails 20 with the HRPP accreditation work. You know, what's 21 the evidence? We don't really have a lot of data that 22 says that that works or how we measure effectiveness 263 1 of IRBs. 2 I guess, is there any interest at the 3 federal level in looking at this, in putting out an 4 RFP? We all know about the IRB enhancement grants 5 that NIH handed out. And a lot of us took advantage 6 of those grants, and they were very, very helpful, but 7 you know, they're gone away now. So there doesn't 8 seem to be any interest in continuing to fund IRB 9 enhancement. 10 I don't know the genesis of those grants. 11 Maybe somebody else does. But again, is there any 12 incentives on the part of various federal agencies to 13 say, "You know, this is important. We need to get 14 some data." Or is this not something that's even on 15 the radar screen? 16 DR. FLANZER: I can only give you my 17 opinion. 18 DR. PRENTICE: Okay. 19 DR. FLANZER: I don't think it's on 20 anybody's radar screen particularly. And it's not 21 something that the agencies are going to do on their 22 own. I think the -- I don't know the origin of the 264 1 IRB enhancement grants, but I think that was a 2 bioethics center issue. Am I right, Sarah? 3 DR. CARR: Actually, that was a 4 coordination, a program coordinated at the central 5 level by the extramural research program. And it was 6 a one-time -- funding was available on a one-time 7 basis, and, you know, I don't think there are any 8 plans to renew that or offer additional funds for 9 that. 10 DR. PRENTICE: Ada Sue. 11 MS. SELWITZ: You know, that initiative 12 came out of Wendy Baldwin's office. And she was 13 chairing a regulatory burden committee. And the idea 14 initiated I think predominantly with Wendy, but 15 through that committee, and then she worked with NIH 16 to get funding from the directors and they funded one 17 year. And then they funded a subsequent year. 18 And this is maybe going in a different 19 direction, but since you mentioned that, one thing 20 that I had hoped that at some point SACHRP would do is 21 ask the program officer from the NIH enhancement 22 awards to come and share with us the kinds of things 265 1 they've learned and what they thought. 2 And even then in the long run I was hoping 3 that maybe SACHRP would look into whether it's a 4 recommendation that a similar program be offered 5 again, because it certainly, I think, has been of 6 tremendous value to strengthening human subjects 7 protections. And I would love to see that program 8 offered again through NIH or some other. 9 But I think it's also an interesting idea 10 to try to get at the systems approach through 11 something similar. I do know that initiative because 12 I was on the regulatory burden committee at the time, 13 took considerable effort within NIH to get the 14 funding, but they did achieve it. And it was funded 15 by all the institutes; I believe that's correct. 16 DR. PRENTICE: Okay. Thanks. Okay. Like 17 all of the other priorities, we're certainly going to 18 think about them very seriously. And OHRP, I'm sure, 19 will have discussions about those and we'll see where 20 we go in the future. So I -- yes. 21 DR. JONES: Sally, you talked about not 22 only the mechanism for getting researchers in the 266 1 community to look and be attracted to these topics, 2 but how do you enable federal agencies to look at 3 their own data? Are there mechanisms? How do you 4 make that a priority for agencies? 5 DR. PRENTICE: What data? 6 DR. FLANZER: The process data, I think is 7 what you mean. That generally happens at the agency 8 level when you're asked to justify part of your 9 budget. And you have to make the case that you need 10 an assistant or you need something, so that's when you 11 count. This is not something that the agencies, 12 except for NIH Office of Extramural Programs, and NIH 13 in the intramural office which runs 14 IRBs themselves 14 -- I'm sure that NIH intramural can tell you a lot 15 about what they do. 16 But it's not something the agencies share 17 only because no one seems to ask them to share it. 18 There's no place that you come for that kind of 19 information. So not much is collected, and there's no 20 place to share it. 21 Ernie, I have one sort of different 22 comment to make. And that is that this is a -- I 267 1 think what I'm presenting as a topic is very different 2 from the kinds of things that SACHRP has been pursuing 3 to date. Rather than dealing with the sort of -- the 4 substantive fine grained approach to the regulations 5 and to their enforcement, I'm really talking about a 6 tree top, systemic look across all of government. 7 And that's -- I'm a little person down on 8 the totem pole, but you're a secretarial advisory 9 committee and you could make an impact that's not just 10 -- that's sort of outside the regulatory box that you 11 talked about before. You could bring this question up 12 to the level of the research enterprise. But I do 13 recognize it's a different kind of task. 14 DR. PRENTICE: Okay. Well, I'd like to 15 thank you, Sally. We've got, obviously, a lot on our 16 plate to think about, do we not? The day is getting 17 long. We've got people that have to go fly off 18 someplace. So are there any other questions before we 19 go into the last segment of our meeting? Any 20 questions for Sally or anybody else? Yes. 21 DR. WEINER: I guess I don't want Sally to 22 leave her discouraged because we haven't jumped at her 268 1 idea. As a former researcher and as a public person 2 and whatever, I think it's very, very important to 3 resolve this. 4 The question is, the theme that you raised 5 earlier, which is where the home for it. And it's not 6 clear to me that the home is here, but that doesn't 7 mean that you should stop looking for its home. 8 DR. PRENTICE: No. I agree with you. I 9 think it's very important as well. As a matter of 10 fact, it's been important for a long time. This is 11 not something new. This is really something old 12 that's never been pursued. Really, the issue is 13 where's the best home and what role might SACHRP play. 14 And that's still not totally clear. That's going to 15 take some further thought and discussion, I think, on 16 our part. But Sally, we thank you for your comments 17 and your presentation. 18 Any other questions, comments? 19 Okay. We did have a public comment 20 section scheduled for 4:15. I know that there's one 21 individual who would like to address us. Once again, 22 there may be others, so I would like to now move into 269 1 a public comment section. John, I know you're on the 2 list. 3 PUBLIC COMMENT 4 MR. MATHER: John Mather, vice president 5 Chesapeake Research Review. I just want to make a 6 couple of comments. One has to do with the subject 7 you were just discussing, and the second one is maybe 8 a different take again on an area for exploration. 9 Time and time again, I've come to SACHRP 10 meetings and we seem -- or you seem to be foiled on 11 the issue of data. Not fancy, analytical work, but 12 just simply descriptive data, like the way the world 13 looks today. 14 And so I think that feeds into what Sally 15 put on the table, that there is no clear focus 16 throughout the federal government except in the area 17 in which they have responsibility. OHRP with the 18 FWAs, for sake of example. Or telling all the IRBs 19 and giving descriptive data on IRBs. But then right 20 behind you is the VA that happens to have 116 FWAs and 21 many more IRBs. 22 So, I mean, I don't even think we're at 270 1 first base on this in terms of descriptive data, and 2 then going onto analytical ways of looking at things, 3 and then sort of a synthesis that pulls it all 4 together. Sometime or another it seems to me you've 5 got to start. And I'm reflecting on the discussion we 6 had a little bit a moment ago about accreditation and 7 the effectiveness of accreditation. 8 Well, you know the last -- the second of 9 the two IOM reports that dealt with human subject 10 protection which is now like three years ago, there 11 was a whole chapter in there about the federal 12 government ought to do this with respect to collection 13 of data on accreditation; the private sector ought to 14 do this, et cetera, et cetera. Where does that go? 15 It sort of sits right there I think. 16 So my plea is sometime or another that we 17 just realize that this is a cross agency issue, and 18 maybe this is exactly where you need some sort of 19 subcommittee to pull together what Sally put on the 20 table as it were as a teaser, and then really think it 21 through. What is the responsibility for having data, 22 so we do know that everything that we do, regulations 271 1 or whatever it is, does in fact proceed to help in the 2 protection of human subjects. 3 Time and time again, I sort of think to 4 myself, "Gee, wouldn't it be nice to have that piece 5 of critical data that would help the Subpart A to make 6 a rationale decision as opposed to an expert choice." 7 It's not to say an expert choice isn't a good thing. 8 There are some smart people doing that. 9 But I'm sure there's a sort of a sense as 10 a researcher that you'd like to have a little bit more 11 confidence maybe about what -- the directions you're 12 going. It's going to make real, real sense in the 13 long run, and you're not going to deal with untoward 14 consequences. 15 Okay. My second point is one which is a 16 little difficult to state, but we heard a discussion 17 about needing to hear from investigators. I'd also 18 say we need to hear from participants, but even more 19 important there is this nexus between the investigator 20 and the participant. 21 Here we want the investigator to have 22 respect for the participant and we want the 272 1 participant to trust the investigator as to what 2 they're getting involved in. I mean, there is an 3 interaction, a compact, between the investigator and 4 the participant. 5 And it seems to me all other things, 6 whether it's the IRB or the institution, is hoping 7 that that interaction is working effectively, and is 8 in fact to both advantage, the investigator and the 9 participant. 10 I mean, I've been to places where there's 11 a bill of rights for participants. And I'd like to 12 know where all the bill of rights are that I've seen. 13 I mean, many places have simply finally done that and 14 said, "You as a participant have this right." I've 15 been to other places where there's a code of ethics or 16 responsibilities for investigators. And if you as a 17 investigator do not fulfill this, you're toast in this 18 institution in terms of being an investigator. 19 I mean, that's just kind of an interactive 20 thing that I know we don't have data on. And I 21 personally have information on that kind of a thing, 22 which is where the rubber hits the road. It's that an 273 1 investigator, participant interaction I'm trying to 2 focus on. I don't know how we do it. 3 If you had a panel of investigators and 4 participants, it would be fascinating. But unless 5 it's the investigator with that particular participant 6 in that particular research study, I'm not sure we 7 gain a lot of information. In fact, I'm not even sure 8 we gain a lot of information anyway. 9 We talked about the informed consent 10 process, and we talked about the informed consent form 11 or document. That's an interaction issue between the 12 investigator and the participant. And that's where I 13 think the protections need to be. Whether you have a 14 panel on that, I don't know, whether you want to 15 explore that. But that to me is a very important area 16 to explore. 17 DR. PRENTICE: Okay. Thanks, John. 18 You're right. We don't have a lot of data. We don't 19 know what goes on in those 4,000 or 5,000 IRBs. We 20 simply don't. Again, this is something that we need 21 to weigh in terms of what involvement could SACHRP 22 have on this. It sounds to me like we need a huge 274 1 study to try to get data across institutions. 2 As you mentioned, how many institutions 3 have a bill of rights? Well, we got one. I know 4 California has got one that's a state bill of rights. 5 I couldn't tell you whether or not any other 6 institutions hand out a bill of rights to research 7 subjects. Is that good practice? Maybe. Maybe not. 8 I don't know. Okay. 9 Would I like to know that 80 percent of 10 the institutions out there that have an FWA have such 11 a bill of rights because I think it's a good idea? It 12 would be nice to have that data. Then we could see 13 whether or not it's a good idea. So you're right; 14 there is no data. We just don't know how well the 15 system works. 16 We know how well it breaks down, when we 17 have an incident that causes the federal government to 18 go in and find out what happened. Then we know the 19 system didn't work at that particular institution, but 20 all the rest institutions it's hard to get a handle on 21 it, isn't it? 22 Any other comments from the public? Yes, 275 1 please. 2 MR. BROADHEIM: Hello. I'm Jeff Broadheim 3 from the Department of Education, just speaking in a 4 personal capacity. I want to make clear that we 5 really don't want to get lost on the issue of mega- 6 study. Clearly, I wouldn't want us to have a giant 7 study that covers everything and tells us everything. 8 That's not going to happen politically, financially, 9 otherwise. 10 What we do know is that there have been a 11 fair number of studies out there. I've got something 12 about 180 articles, for example, that are reporting, 13 empirical studies of IRB operations and impacts. So 14 there is some information. There is a lot of things 15 that can be done in the context of existing studies, 16 small modules with data collections. 17 For example, census repeatedly collects 18 information embedded in their studies about their 19 study procedures. It's very routine process for the 20 agencies to collect this. 21 What we would find very helpful is a sense 22 of whether SACHRP thinks that evidence would be 276 1 helpful in some areas and what sorts of priorities 2 would be there. And perhaps supporting that, if some 3 entities were able to provide background and 4 assistance such as national research council/IOM or 5 somebody to help clear the brush away to say what we 6 know, what we don't know, what we need to know. 7 I'm somewhat impressed by what we've seen 8 in the area of medical accident reduction work over 9 the past couple of years. It was essentially a non- 10 issue for most people. I've seen tremendous progress 11 over the last several years following various 12 articles, various IOM reports. I think that we can 13 see large impacts and improving protection of human 14 subjects, both in terms of making them more effective 15 and helping to eliminate unnecessary burdens that can 16 not only burden studies, but create invalid and 17 dangerously misinforming studies in the process. 18 So I think that we can get a lot of 19 leverage with fairly modest results -- fairly modest 20 research in a fairly small amount of time. And SACHRP 21 can help focus attention on what we know, what we 22 don't know, what we need to know. Thank you. 277 1 DR. PRENTICE: Okay. Thank you very much. 2 Felix. 3 DR. GYI: I think that's a great point. 4 You know, clearly there's been some funding from NIH 5 regarding ethics committees and there's are some 6 training grants that have dovetailed into research 7 activities as well. But I think when we talk about 8 data, we're looking at things like the QI/QA types of 9 information that would truly give us some meaningful 10 outcomes type of issue. 11 But you reminded me of a thought that 12 perhaps we ought to have a synthesis of the available 13 information to see what the void really looks like. 14 And maybe that ought to be the next step, to see where 15 that is. But who does that? I mean, clearly we're 16 not going to do it. But who would do that? Who would 17 take those 180 articles and do a meta-analysis? 18 MS. SELWITZ: Isn't that what Sally's 19 proposing, is that there be some centralized group set 20 up to do it? It's just there isn't any group 21 available at this point. And I thought, Jeff, your 22 comments were well taken and fit nicely with the -- 278 1 you know, articulated something that does need to be 2 done. 3 DR. PRENTICE: Okay. Yes. 4 DR. FLANZER: The feds aren't like an 5 academic institution. I mean, I don't have any 6 research assistants. I don't even have summer interns 7 anymore that can do this. 8 But routinely, you can get contract -- you 9 can write a contract for a literature review, and 10 agencies do that before they put out a new grant 11 offering so that the agency people have a sense of 12 what's out there and what are the questions to ask. 13 So that -- a research synthesis of the existing data 14 is actually a good first -- I think it's a good first 15 step, and it's a small manageable first step. But 16 somebody still has to pony up the money for it and be 17 the contract officer. 18 DR. PRENTICE: Okay. Any other comments? 19 All right. Well, let me bring this meeting to an end 20 by simply thanking everybody for their participation. 21 We've had a -- you have a question? 22 DR. WEINER: How do we decide on the 279 1 priorities? 2 DR. PRENTICE: We are not going to, I 3 think. We're going to, with your indulgence, we're 4 going to discuss these with OHRP and their staff and 5 think about what we can handle and what we can't 6 handle because there is a limit in terms of staff 7 support for our activities. And this is what has to 8 happen before we can actually start establishing these 9 kinds of priorities. 10 This is a little bit different than taking 11 on Subpart D or Subpart C. You know, that's fairly 12 straightforward. This is not so straightforward. 13 This involves -- some of these considerations involve 14 multiple agencies within the federal government. We 15 just can't simply say, "Okay, this is what we're going 16 to do." 17 There are other considerations that have 18 to be brought to the table by people who are involved 19 in the federal government. And I'm certainly 20 obviously not. So I think that we have to give Bern 21 and his staff an opportunity to consider some of these 22 issues, and say, "Okay, how can SACHRP work with OHRP 280 1 and work with other federal agencies to then pursue 2 some of these issues that we have talked about?" 3 We've got some ideas. We've got some 4 ideas for some panels that we can certainly think 5 about. We will consult with you about these panels as 6 we get more solidified ideas about what we should do. 7 We basically have one day at each SACHRP meeting to 8 have a panel or multiple panels. That's all we got. 9 The other day, the first day is taken up with 10 subcommittee reports. So we have to decide on that. 11 Looking at Joan's comments about getting 12 the data, we have to look at when is the data going to 13 be available; is it going to be -- is that report 14 going to be available in time to present to SACHRP? 15 Or is that premature? Maybe they're not going to have 16 a chance to analyze the data, so we got to get a 17 handle on that. 18 We've got to look at -- if we decide to 19 invite the pharmaceutical companies to come in, we 20 have to look at those issues. Who is going to get 21 invited? Okay. Are you just going to pick the top 22 three? I don't know. 281 1 These are considerations that we don't 2 have time obviously, unless you want to stay here 3 until 10:00 tonight, and I don't think you do, to 4 think about. So we'll progress in our thinking and 5 we'll consult the members of SACHRP as we try to 6 develop agendas, as we've done in the past, as you 7 know. Okay. 8 DR. WEINER: It would be good to have some 9 interim sort of status report discussion about where 10 things are between now and March. That's a long time 11 away. 12 DR. PRENTICE: You mean like a -- 13 DR. WEINER: Let us know what's going on. 14 DR. PRENTICE: We always let you know 15 what's going on, Susan. Okay. You know that. Yes. 16 Where are we? Who else? Somebody else got their hand 17 up? You do. Okay. 18 MS. STITH-COLEMAN: I just wanted to 19 report to you that about the CIRB evaluation, that 20 it's going to start in several weeks and the hope is 21 that will be completed in six months. 22 DR. PRENTICE: Yes. Any other -- 282 1 DR. JONES: Ernie, also, you know, we've 2 had some different comments about that the composure - 3 - composition of SACHRP is going to change 4 dramatically, too. So I think, like you have 5 suggested, that it's important not to start a new 6 subcommittee to also reflect on what else might come 7 from new perspectives, to what are some other 8 priorities that we might consider. 9 But I would like to endorse that I think 10 the topics that are on the table are all important, 11 and that whatever we can do to not let them die is a 12 good thing, if it's -- I don't think we're ready to do 13 a subcommittee just given where we are and the 14 timeframe of SACHRP. But I do think that if we can 15 keep some of these topics, or at least invite people 16 back, or ways to say that we recognize that these were 17 important things that were brought to us today and 18 that we want to see them to move forward. 19 DR. PRENTICE: I totally agree. If you 20 think about the progression of SACHRP's consideration 21 of the issues, we have gone back a number of times to 22 look at issues that were brought to our attention by 283 1 various panels. The principal example that comes to 2 mind, of course, would be the adverse event problem. 3 That keeps on coming back; we keep on getting reports; 4 we're clearly making progress. 5 International research, that's always been 6 a priority. The question is: when does SACHRP step 7 in? And we're not there yet, I don't think. My 8 personal opinion is I would really love to see this 9 data or find out what's not there. That would give us 10 an idea of perhaps a direction that we want to move 11 in. 12 Comments about having investigators come 13 in with creative ideas, okay. Well, we've certainly 14 had IRB administrators come in; we've had IOs come in; 15 we've had subject advocates come in; we've had human 16 research subjects come in and address us. There's 17 nothing wrong with having investigators come in and 18 say, "Listen, this is kind of what we think." That's 19 fine, too. We can look at that and decide, well, when 20 would be the most appropriate time to have that happen 21 in terms of that second day of our meetings. 22 There are other things that have been 284 1 brought up here that are sort of like on the table. 2 And we just have to decide what should we address 3 first. And I don't really think that SACHRP, at least 4 my impression is, nothing is at the top list that you 5 say, "This is absolutely paramount. This has to be 6 addressed at the very next SACHRP meeting." I haven't 7 seen that from anybody. You said all of this stuff is 8 important. Right. Is that not right? We just can't 9 do everything. 10 A second Subpart A Subcommittee, I mean, 11 look how much you have to do, Felix. You're going to 12 be on Subpart A for the next 20 years. Well, maybe a 13 second subcommittee might be good, but then you got to 14 look at issues as OHRP staff -- they're understaffed 15 right now; you all know that. And they provide a lot 16 of support for us; they do a lot of work for us. 17 We've got to look at that consideration. 18 We have to look at well, could these two - 19 - how would they coordinate? Are they going to meet 20 periodically together? And then you're looking at 21 resources. So these are not easy issues to just say, 22 Okay, this is what we're going to do right now." We 285 1 can't do that. We've got to think about it for a 2 while and say, "Okay, what's the best way to 3 progress?" All right. Fair enough. Everybody happy? 4 That's good. 5 Okay. I was about to bring this to a 6 close, but I forgot what I was going to say. So let 7 me try to say something else. 8 Every time I come to one of these 9 meetings, I am so struck with the quality of the 10 conversation and the commitment of SACHRP members and, 11 of course, reflected by all of your workgroups and all 12 of the people who are behind the scenes or aren't here 13 to do a lot of work; the involvement and commitment of 14 OHRP staff who work hand-in-hand with us; the 15 involvement and commitment of the ex officio members; 16 and the participation of people who are just within 17 the federal government and are not directly involved 18 in what we do. 19 I come away thinking that, you know, we're 20 making progress here. And boy, if we can say that 21 every time we meet, if we can, you know, "We've taken 22 a step in the right direction," then I think we've 286 1 accomplished something. 2 So I thank you for everything that you've 3 done. And I'll see some of you at PRIM&R, and for 4 those who I don't see at PRIM&R, have a happy holiday 5 to everybody, and we'll see you next March, I guess. 6 Okay. Thanks. Meeting is adjourned. 7 (Whereupon, proceedings in the above- 8 entitled matter concluded at 4:00 p.m. on November 2, 9 2005) 10 11 12 13 14 15 16 17 18 19 20 21 22