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: