1 DEPARTMENT OF HEALTH AND HUMAN SERVICES SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION MEETING MONDAY MARCH 29, 2003 The Advisory Committee met in the Commonwealth Ballroom in the Holiday Inn Hotel and Suites, Commonwealth Center, 625 First Street, Alexandria, Virginia, at 8:30 a.m., Ernest Prentice, Ph.D., Chairman, presiding. MEMBERS PRESENT: ERNEST D. PRENTICE, PhD, Chair BERNARD A. SCHWETZ, DVM, PhD, Acting Executive Secretary CATHERINE SLATINSHEK, MA, Executive Director THOMAS L. ADAMS, CAE Member MARK BARNES, JD, LLM Member CELIA B. FISHER, PhD Member ROBERT G. HAUSER, MD Member NANCY L. JONES, PhD Member FELIX A. KHIN-MUANG-GYI, PharmD, Member SUSAN KORNETSKY, MPH Member MARY L. POLAN, MD, PhD, MPH, Member SUSAN L. WEINER, PhD Member MEMBER ABSENT: E. NIGEL HARRIS, MPhil, MD, DM EX OFFICIO MEMBERS: HOWARD L. BRADLEY Social Security Administration FRANK BRICKFIELD U.S. Central Intelligence Agency KATHRYN LYNN CATES U.S. Department of Veterans Affairs ROGER CORTESI U.S. Environmental Protection Agency PATTY DECOT U.S. Department of Defense ANITA EISENSTADT, JD National Science Foundation SALLY FLANZER Agency for Healthcare Research and Quality DAVID LePAY, MD, PhD Food and Drug Administration DAVID SHORE National Institutes of Health 2 OHRP STAFF PRESENT: MICHAEL CAROME IRENE SMITH-COLEMAN PAT EL-HINNAURY KELLEY BOOKER JULIA GOREY KARENA COOPER KRISTINA BORROR RINA HAKIMIAN SHIRLEY HICKS JUDITH BROOKS JULIE KANESHIRO GLEN DREW MELINA HILL CARLA BROWN 3 I-N-D-E-X Welcome: Opening Remarks. . . . . . . . . . . . . .4 Ernest Prentice, PhD Report on Issues. . . . . . . . . . . . . . . . . .5 Bernard A. Schwetz, DVM, PhD Overview of Charges to Subcommittees. . . . . . . 14 Ernest Prentice, PhD Subcommittee on Research Involving. . . . . . . . 18 Children Report Questions/Comments. . . . . . . . . . . . . . . . 44 LUNCH Subpart C Subcommittee report/issues. . . . . . .123 BREAK Accreditation Subcommittee report . . . . . . . .202 Public Comment. . . . . . . . . . . . . . . . . .221 Summary of day's activities . . . . . . . . . . .230 Adjourn . . . . . . . . . . . . . . . . . . . . .242 4 1 P-R-O-C-E-E-D-I-N-G-S 2 8:36 a.m. 3 CHAIR PRENTICE: This is the SACHRP 4 meeting. This is the charter that we have been given. 5 As you can see, we are being asked to advise Secretary 6 Thompson on matters concerning the protection of human 7 subjects, with particular emphasis on vulnerable 8 subject populations. That indeed has been our 9 emphasis. However, the charter is broader. It also 10 includes issues such as international research which 11 we'll talk about today, research involving 12 identifiable tissue samples, investigator conflict of 13 interest, as well as various activities of OHRP. 14 This is a quote from Secretary Thompson. 15 When the announcement of SACHRP appointment was made 16 to the press on January 3, 2003. And Secretary 17 Thompson said, "We must make sure that we allow 18 science and medical research to advance for the good 19 of all Americans, but not at the expense of the people 20 who participate in clinical trials." So we have tried 21 to remember that quote from Secretary Thompson in our 22 work. 23 These are the members of SACHRP. They are 24 here. You can see all of their name tags. I won't 25 ask them to introduce themselves. The executive 5 1 secretary is Dr. Bernard Schwetz, who is the acting 2 director of OHRP. And our exec. sec. is Cathy 3 Slatinshek. Where is Cathy? Cathy is the individual 4 who just pulls all of this together for us and makes 5 life very easy. 6 We have a number of ex officio members of 7 SACHRP. Dr. Schwetz meets regularly with the ex 8 officio members to talk about issues of comment and 9 concern. So we're grateful for their participation. 10 Next I would like to ask Dr. Schwetz to 11 give us a report on the issues. 12 EX. SECRETARY SCHWETZ: Thank you, Ernie, 13 may I do it from here? 14 CHAIR PRENTICE: Yes, you may. 15 EX. SECRETARY SCHWETZ: Thank you. Good 16 morning to all of you. Let me thank the members of 17 SACHRP, and particularly the members of the 18 subcommittees of SACHRP for all of the hard work and 19 progress that you have made. I've been on a lot of 20 advisory committees in one way or another for the FDA 21 and other agencies, and it seems often that most of 22 what gets done gets done in the meetings. Most of 23 what gets done with this committee and the 24 subcommittees is all of the work that gets done 25 between the committee meetings. And I think that's 6 1 very impressive. So I thank you a lot on behalf of us 2 and others who will benefit from the work that you're 3 doing, for the progress that you're making. 4 But I think it is also important that as 5 I continue to listen to people and talk about what 6 SACHRP is doing as I visit one place or another, the 7 feedback that I get is the issues that you're working 8 on within the subcommittee structure now continue to 9 be very important issues. So I think you are well 10 targeted in picking the subjects that you did, and I 11 know that part of this meeting is to try to figure out 12 how -- where do we go next as we have the opportunity 13 to work on more specific topics. 14 Let me comment a little bit on what I am 15 hearing about OHRP as I visit various institutions and 16 participate in meetings that range from one-on-ones, 17 to with various people, to large groups of people. As 18 I'm out trying to listen to what people want to tell 19 me about OHRP and what it's doing well and what it 20 isn't doing well and what it should be doing, I do 21 hear a lot of good things. But that's not what I want 22 to talk about this morning because that we kind of 23 take home and use as reinforcement for what we're 24 doing and it makes us feel good. But not everything 25 is of that nature that I hear. And some of those 7 1 things is what translates into the changes that we are 2 looking to make within OHRP, and also to help set some 3 of the priorities for the things that people want us 4 to work on, or people want help. 5 One of the things that I hear more often 6 than I like it is from an institutional person who 7 says, `I'm afraid to call OHRP, and I'm afraid not to 8 call OHRP.' And I think that is not totally unexpected 9 or unreasonable, but I don't want us to be seen as an 10 organization that people who could benefit from 11 talking to our individuals don't take advantage of 12 that benefit by failing to call because they're afraid 13 something will get divulged and they'll be in trouble. 14 So I would like to encourage that people would feel 15 free to call OHRP for help. And those who do don't 16 complain to me about having been caught in a trap in 17 the process of being asked for help. So I would 18 encourage that people -- that we would be an 19 organization that people feel comfortable calling to 20 get information. 21 Another thing that I hear a little bit 22 less often, but to hear it at all is not good, that 23 OHRP shuts places down for trivial reasons. And I 24 have sometimes been in audiences where people were 25 from the institutions that were shut down temporarily 8 1 when that statement is made by somebody else, and I 2 don't even have to answer it. They say if you believe 3 that, you're wrong. Because when we got into trouble, 4 it was not for a trivial reason. And in fact they 5 said they wished that OHRP had come and visited us 6 before we found ourselves in that situation because it 7 would have helped. And we may not have been there. 8 So we certainly don't sit around as an agency looking 9 at how can we find somebody next to shut down. That 10 is absolutely not what we're about. But we do hear 11 that comment. 12 Another one is that we need guidance on þ 13 and you fill in the blank. All kinds of things that 14 people want guidance on. And we also hear that people 15 want better guidance. Not just a reiteration of 16 what's in the regulation, but guidance that is 17 understandable and goes beyond what people get when 18 they read the regulation. So that's one thing that I 19 wanted to comment on a little bit more. 20 I'm also getting the comment more often 21 that we need best practices. Knowledge of best 22 practices out there in the community -- and this has 23 been coming particularly in the area of informed 24 consent, where after all these decades we still see 25 that as something that isn't quite right, it isn't 9 1 perfect yet, and there must be some knowledge that's 2 out there that we could pull together to help in the 3 sense of best practices for informed consent. 4 What are some of the changes? One thing 5 is to change our image. We are in the process of re- 6 evaluating within OHRP -- and we'll be talking about 7 this some more in some meetings that we have scheduled 8 for the future -- about the image of OHRP. In the 9 sense that we are a compliance office. There is no 10 question about that. But that isn't necessarily the 11 only image that we want portrayed for OHRP. So we 12 would like to be a source of information. And, 13 incidentally, part of our charge is the compliance 14 function, but just to have everyone know that that's 15 not our only charge. 16 Just some examples of things that have 17 changed internally that create a different image. 18 Several years ago there were as many as 160 open 19 compliance cases. That's now down to 40. That's 20 quite a change just in the number of people that the 21 Office is working with on open cases. And that may 22 become a little bit lower yet, but we may also reach 23 a steady state here. So that backlog has been reduced 24 significantly. 25 I was also in a meeting last week where 10 1 reference was made to the fact that when 407 expert 2 panels are called together to review a protocol for 3 children's issues, that it's like that protocol drops 4 into a black hole. Well, I didn't address the answer 5 then. I didn't answer the question, but in fact the 6 black hole is gone. And that may have been a 7 perception at one time because of the length of time 8 it took to get resolution. Well, at this point we 9 only have one of those expert panel reviews that 10 hasn't yet gone to the Department, and that one's 11 going to go pretty soon. So I think the sense that 12 there's a black hole there, that things never happen, 13 we have improved that as well. 14 Some shifts in priorities. We clearly 15 want to have greater capacity for writing guidances. 16 And to do more QI visits. The writing of guidances 17 from the standpoint that as we've pulled together the 18 information that we have gotten from other agencies 19 under the common rule, or from people out in the IRB 20 community or the investigators, whomever is requesting 21 guidance, when we put that list together it was 22 several pages long. And we don't have enough people 23 to shorten that kind of a list. It's growing faster 24 than we can shorten it. So we're looking at ways 25 beyond FTEs to reduce that list of guidances and be 11 1 able to get some of these guidances out. And I'll 2 come back to you on that because that's one place we 3 want your help. Not to write guidances, but to help 4 set priorities. 5 The other thing is to have more QI visits. 6 As I've talked to people who have been visited by our 7 teams of people for a day and one-half, two days, to 8 review what's going on in your institution and provide 9 feedback, not of a compliance nature but simply 10 looking at how things are operating, we get a lot of 11 positive comments from people who say that was 12 extremely valuable to us in terms of what we heard, 13 but also in terms of bringing our people together in 14 the institution to focus on the importance of human 15 subject protection, to get the right people into the 16 room to reinforce the importance to this. This also 17 ties together with accreditation in the sense that a 18 lot of institutions are looking at QI visits as 19 another preliminary step to considering what kind of 20 shape are we in for accreditation. And in that sense 21 we'd be happy to be out there to more places more 22 often to have our presence known, because we are 23 supportive of the concept of accreditation. And if 24 this can be part of it, that's fine. 25 We are also looking at our education 12 1 program as we've had it for a number of years. And 2 that's been a major investment of resources and 3 people's time within OHRP and our educational 4 programs. But we've never gone back and looked at 5 what impact does it make. We have set aside money 6 this year for a review of what we get out of the 7 educational program, to help tell us which parts of it 8 are most valuable, which parts should we be spending 9 more energies on, and to help use that information in 10 setting our own priorities internally. 11 We're also looking at being involved in 12 public outreach. Because of the fragility of the 13 human research enterprise in terms of the number of 14 people who are willing to be recruited, we feel that 15 we have an opportunity, as part of the federal 16 government, together with other partners within HHS or 17 elsewhere, to try to make the public more aware of the 18 benefits of being involved in human research, but also 19 the risks. And if you're concerned or you're 20 interested, where do you get more information. So 21 we're also looking at a public outreach program. 22 There are some other issues that we've 23 been spending a lot of time on lately. One is the 24 question of the difference between research and non- 25 research, and especially as it relates to public 13 1 health surveillance programs and quality improvement 2 programs where it's very confusing and has been the 3 topic of argument as well as discussion for quite a 4 few years about when does some of this public health 5 surveillance work constitute research and should have 6 gone through an IRB. And same for quality improvement 7 programs. 8 We've also spent a fair amount of time 9 recently trying to figure out what does it really mean 10 when you talk about HHS-funded or supported research 11 in the context of requiring an FWA assurance, 12 especially for outside work, or outside the country 13 kinds of collaborations, where you might have somebody 14 involved here and a number of laboratories in other 15 countries, institutions. And the requirements for 16 FWAs under those circumstances requires that we have 17 to have a clear definition of what falls under the 18 heading of `Funded or Supported.' 19 Well, there are other things, and I won't 20 go on further, except to mention a couple areas where 21 we in particular would ask for help, and this will be 22 part of the discussion tomorrow. Help in providing 23 guidance on what are the real questions and how do we 24 deal with the questions that surround tissue and 25 databanks. This question of research versus non- 14 1 research, priorities for guidance. I would like, not 2 necessarily in the context of tomorrow's meeting, but 3 in one of the future meetings of SACHRP to bring some 4 of what we've been hearing from other federal 5 agencies, and what we hear from the community that we 6 interact with about priorities for guidances, at least 7 the list, and what you see as priorities from your own 8 experience. And work those together so that we would 9 be working from a list where it's not just our opinion 10 of which ones are more important, but we have a lot of 11 help from some of the rest of you. So as we take on 12 more guidances, that we have your input. 13 And also the question that we continue to 14 discuss: Are there changes that should be made to 15 Subpart A, and if so what are they? What are the 16 priorities for them? So these are some of the things 17 that we've talked a little bit with with Ernie in our 18 discussions. And maybe we'll have a chance to talk 19 about those some more tomorrow. Thank you, Ernie. 20 CHAIR PRENTICE: Thank you, Bern. I have 21 a new microphone set up here you need to be aware of. 22 When I press the right button I get to speak. When I 23 press the left button I cut you all off. So be 24 forewarned that you have to behave and stay on time. 25 All right, for the benefit of the audience 15 1 I don't think that the members of SACHRP need to have 2 an overview of what your charges are. You've been 3 working on them diligently. We have three 4 subcommittees, the first one being the subcommittee on 5 research involving children. And the initial charge 6 was to provide recommendations for consideration by 7 SACHRP on the Subpart D 407 panel review process that 8 was referred to by Dr. Schwetz a moment ago. That is 9 the 407 required panel when an IRB is unable to 10 approve a research protocol under the other categories 11 within Subpart D, i.e. 404, 405, or 406. It's got to 12 be referred to the level of HHS for review. 13 So we've been looking at this 407 panel 14 review process to try to achieve a number of goals, 15 i.e. transparency, public input, expert input, having 16 this clarity, and harmonization with OHRP and FDA 17 because FDA also has an equivalent Subpart D 18 requirement. And then to provide ultimately 19 recommendations on exactly how we interpret the 20 requirements of Subpart D. NHRPAC had looked at that, 21 and had to begun that process. And we're certainly 22 utilizing what they have done. And the IOM has also 23 been looking at research involving children. So the 24 co-chairs for this subcommittee are Sylvia Fisher and 25 Susan Kornetsky. And then we have a number of 16 1 additional members on that committee drawn from the 2 broad-based research community. 3 The second subcommittee that we have 4 appointed would be the Subpart C subcommittee, which 5 is looking at additional protections for prisoners. 6 And the initial charge to that subcommittee would be 7 to provide recommendations for consideration by SACHRP 8 on interpretation, or reinterpretation, and perhaps 9 ultimately a total revision of Subpart C to ensure 10 that regulations do not obstruct ethically and 11 scientifically appropriate research. There is some 12 concern that the current Subpart C is just simply not 13 working appropriately. It was issued in an era that 14 is distinctly different from the current era that we 15 live in today. So the co-chairs are Mark Barnes and 16 Nancy Dubler. 17 The third subcommittee would be the 18 accreditation subcommittee. And the charge for that 19 subcommittee is to provide recommendations for 20 consideration by SACHRP on the following aspects of 21 HRPP, which means Human Research Protection Program 22 accreditation. As you undoubtedly know, we don't 23 refer to human subject protection simply in terms of 24 an IRB anymore. It's an entire program. And that 25 subcommittee was asked to look at the perceived value 17 1 of HRPP accreditation. What incentives exist or 2 should exist to motivate institutions to seek HRPP 3 accreditation. To take a look at ways of assessing 4 the impact of accreditation. And the process of 5 accreditation has just begun, so I'm sure the 6 subcommittee will be talking about that. And then 7 should the federal government have any role in HRPP 8 accreditation, whether it's oversight, or 9 certification, or what have you. So we're going to 10 have a report from that subcommittee, and the chairs 11 are Tom Adams and Felix Gyi. 12 So let's go over the agenda for today. 13 It's an ambitious agenda. At 9:00, and we're just 14 about right on time, we will have the subcommittee on 15 research involving children's report. Then at 10:30 16 we'll take a very short break. Then we're going to 17 continue with the subcommittee's report on children at 18 10:45. At 11:45 to 12:45 there will be lunch. There 19 is a hotel dining room here, and there is also 20 restaurants straight down the street. We'll begin 21 again at 12:45 with the Subpart C subcommittee report. 22 A break at 2:45. 3:00, the accreditation subcommittee 23 report. And then at 3:45 we would invite public 24 comment. If you would like to comment, we would 25 invite you to put your name down on a list. You will 18 1 be limited in terms of time to five minutes. At 4:30 2 to 5:00 we'll have a summary of the day's activities. 3 Okay. Celia? 4 DR. FISHER: Okay. Susan Kornetsky and I 5 are the co-chairs of the subcommittee on children. 6 And this is our second report. And as you can see, we 7 have a very large committee, many people who visit. 8 Susan Weiner is one of the members. I wanted to 9 underscore Dr. Prentice's remarks that we þ it's not 10 on, now? Yes? Okay. I wanted to underscore the 11 partnership that we have with OHRP, Dr. Schwetz, Dr. 12 Carome, Cathy Slatinshek, and we've been working very 13 closely, and they are incredibly helpful and 14 wonderful. 15 Our meeting goals were twofold. This 16 seems a lot simpler than what you're going to see we 17 actually did. So the first was to develop final 18 recommendations for the 407 process. And the second 19 was to begin the review of the Subpart D terminology. 20 We're going to do the 407 process first. And we have 21 I think six different areas, five or six different 22 areas of recommendations. And the chair requested 23 that we go through the history and background of all 24 of them with the recommendations, and then Susan and 25 I will come back to having the recommendations on the 19 1 slides for discussion. But this way you can see the 2 whole package before we discuss the recommendations. 3 Now, just as a reminder, the first couple 4 of slides are just reminders from our last meeting. 5 What is the 407 process? It's research not otherwise 6 approvable which presents an opportunity to 7 understand, prevent, or alleviate problems affecting 8 the welfare of children. Last time, SACHRP endorsed 9 the committee's recommendation that the process is 10 important. It's important because it ensures not only 11 protections of participants in pediatric research, but 12 it helps ensure that important research with children 13 is going to be conducted. 14 SACHRP also endorsed, as Dr. Prentice 15 summarized, the subcommittee had come up with goals 16 for any recommendation. And these are the goals of 17 transparency, public input, expert input, timeliness, 18 clarity, consistency, and consensus, and 19 harmonization. And so all of those goals guide our 20 recommendations. 21 Last time, we recommended a certain number 22 of steps that SACHRP endorsed, and also OHRP agreed to 23 adopt to try to streamline the procedure. First, to 24 provide increased guidance for IRB application 25 procedures for the 407 process. We approved an 20 1 algorithm that at some point I think will be very 2 helpful for that OHRP endeavor. We worked with OHRP 3 to develop a screening process with respect to 4 applications coming in, and the kind of feedback that 5 OHRP would give, the importance of a public comment 6 review prior to an expert panel meeting about the 407 7 process, and that the public comments would be 8 available to the expert committee. We also endorsed, 9 as did SACHRP, that panel members, whatever model we 10 would adopt, would meet face to face so that they 11 would discuss with each other the different points of 12 view, that this meeting would be open to the public, 13 that there would be web postings of the expert's 14 recommendations, and when appropriate the Secretary's 15 decision and rationale would also be public. All of 16 this helping for both increasing transparency and 17 public input. 18 At that meeting, at our, I think, December 19 meeting, SACHRP requested that we move forward and 20 provide recommendations for what appeared to be the 21 best model for a 407 process, which was the non-FAC 22 open panel model. They also asked us to define the 23 public member role, to review the possibilities for an 24 FDA and OHRP harmonization, to review options for 25 multi-site studies, and how we were going to, or how 21 1 SACHRP could monitor these enhanced processes. 2 So these are the four models that we had 3 been asked to -- that we did review last time. SACHRP 4 preferred the non-FAC open panel, and asked us to 5 provide a rationale for why that might be the best. 6 What our subcommittee decided to do was to also add 7 for comparison an independent FAC model, just for 8 review of 407. Even though the feasibility of that is 9 probably zero, we wanted to make sure that there was 10 no stone left unturned, that the recommendation was 11 fully informed. 12 So what I've done here, and Susan and I 13 have put together, is the three different models. 14 There's the SACHRP subcommittee model. That would 15 mean that SACHRP would appoint a subcommittee that 16 would review a 407 procedure and then it would come 17 back to SACHRP for a decision. There's the non-FAC 18 open panel that is not permitted to give consensus. 19 And there would be an independent FAC model which 20 would have a consensus document. 21 So what would be similar about the three 22 models was that the IRBs, based on the screening model 23 that we had already proposed, a panel would only see 24 an appropriate IRB submission based upon the guidance 25 from OHRP, and the IRB would have to provide 22 1 justification for why a protocol did not meet the 404, 2 405, or 406 standards, that it had scientific validity 3 and social value, that they believe the human 4 subject's protections were adequate. And one of the 5 points that was very important to our subcommittee, 6 and I think to underscore, is that whenever an IRB 7 submits a 407, it is endorsing the fact that it 8 believes the protocol should go on. But they don't 9 have the authority to approve that protocol. OHRP 10 would screen all of the applications, be able to send 11 back feedback to the IRB. There would be a Federal 12 Register notice so that the public would be aware of 13 the review. All the panel members would meet face to 14 face to express opinions at a public meeting. Public 15 comment would be available to them. OHRP would then 16 develop recommendations based on all the materials, 17 forward it to the HHS secretary, and the HHS secretary 18 would make a decision. 19 So all the models incorporate that. How 20 they differ is as follows. The non-FAC open panel 21 could not have a consensus, but it could forward 22 independent panel recommendations that would be on the 23 website. The subcommittee FAC could have a consensus 24 that it would forward to SACHRP, and the independent 25 FAC would have a consensus document. 23 1 Next line. As you can see, a major 2 difference -- there are two major differences. The 3 subcommittee FAC model would be a very long process. 4 The two other models, the non-FAC open panel, and the 5 independent FAC, would only require one meeting. 6 Whereas the subcommittee FAC would require at least 7 two meetings because SACHRP would have to meet. The 8 consent that there would be two opportunities on a 9 SACHRP subcommittee model for public comment because 10 the public could comment at the SACHRP meeting. Okay, 11 I think we can go on. 12 So we attempted to evaluate these three 13 models on the basis of our goals. The first being 14 timeliness. The non-FAC open panel, as I said in the 15 independent FAC, were much more timely because it only 16 required one meeting, and not having to go through the 17 SACHRP subcommittee again. Transparency and input: 18 all models would have expert input, public input, and 19 decisions would be posted on the web. In terms of 20 continuity, the SACHRP subcommittee model and the 21 independent FAC model would have continuity in the 22 fact that they would have appointed set panel members, 23 but the open non-FAC panel could have potentially 24 better expertise given the variety of protocols. The 25 consensus differed in that the non-FAC open panels 24 1 cannot have consensus, whereas the others can. 2 However, in our discussions, and Dr. Schwetz also 3 pointed out that a consensus document does not 4 necessarily provide the public transparency of 5 disagreement or fine points that may have arisen, 6 although a minority report is always available as an 7 option. So that in fact the public end would have 8 more information if independent panel member comments 9 were there. In addition, OHRP will never make a 10 recommendation simply on the basis of a consensus 11 document from a panel, but rather will use that 12 document along with other information. So that the 13 value of consensus, a consensus document per se, did 14 not appear to be a priority. In addition, the fact 15 that independent panel reports could be reported on 16 the web might also assist the process of harmonization 17 because the FDA and the public, and perhaps other 18 agencies, would have available this diversity of 19 views. 20 So our recommendation with the rationale 21 is that SACHRP approve for adoption by OHRP the non- 22 FAC open panel model for 407 review, including the 23 steps that we outlined. Our rationale is as follows 24 and I won't repeat it because I just gave the 25 rationale. 25 1 Okay. Now we move on to the next phase of 2 the 407 process, assuming that SACHRP adopts the non- 3 FAC open panel, but even if SACHRP doesn't, all of 4 these issues remain. 5 So how to define the public member. The 6 subcommittee, first of all, endorsed the need for 7 public representation on 407 panels. The subcommittee 8 discussed who is best to represent the population that 9 is going to be participating in the study. And it was 10 the belief of the subcommittee that it was family 11 members who were in the best position. And we 12 discussed the difference between somebody representing 13 the interest of family members and somebody who was 14 actually a family member themselves, and we endorsed 15 the notion of a family member. 16 Now, we also talked about what happens 17 when -- some of you may recall from our last meeting 18 that we talked about the expertise of the panel, 19 having ethics expertise, having scientific expertise, 20 having public interest and family expertise. And we 21 discussed the fact, what happens if someone who has 22 been chosen as a scientist is also a family member of 23 the child population that is going to be under 24 investigation. Can that person play the dual role? 25 And we decided that that was probably not appropriate 26 1 for two reasons: one is an issue of transparency, how 2 would the public know what role that individual was 3 representing, and also it would dilute in fact 4 potentially the family member representation or the 5 science representation because that person was wearing 6 two hats. 7 So our conclusion was that at least one -- 8 our recommendation is that one public member should be 9 a family member, with the understanding that other 10 family views can be represented at meetings, and that 11 there are also public meetings that families can come 12 to. In addition, we also recognize that sometimes 13 there may be a child population that doesn't have a 14 disorder. And in that situation, we would recommend 15 that at least one public member be a child advocate. 16 Okay, so the specific recommendation is that one 17 public member, at least, come from a family of the 18 specific population to be involved in the research. 19 Number two, that when feasible and 20 appropriate, more than one public member should be on 21 a 407. We did not want to go above the number one 22 because in our discussions at the meeting previous, 23 the ability to be timely and also get enough diversity 24 that one needs in terms of ethics, public member, and 25 science, can be quite difficult. And so we did not 27 1 want to have a specific number over one endorsed. In 2 some cases, there are going to be some protocols in 3 which different types of childhood disorders are 4 there, and in those we would recommend, but not 5 require, that more than one family member be on panel. 6 When the protocol does not include a specific 7 disorder, we recommend that the public member be a 8 child advocate, and that individuals do not serve in 9 dual roles. 10 Next is OHRP/FDA harmonization. Now, as 11 many of you are probably aware, OHRP has a very 12 similar regulation 50.54 that are similar to OHRP 407. 13 I think one joint review has been conducted, and more 14 are anticipated. The FDA is still developing its 15 procedures for implementing its 54. And the 16 jurisdiction involving recommendations to the HHS 17 secretary and the FDA commissioner may differ. 18 Whereas OHRP may make recommendations directly to the 19 secretary, it does not have a direct line to the FDA 20 commissioner. 21 An FDA pediatric FAC has been authorized 22 by Congress. And this FAC may or may not ultimately 23 be responsible for FDA reviews. So we had to take 24 into account that the FDA may have a FAC. And if 25 SACHRP adopts the non-FAC panel, OHRP will be using a 28 1 non-FAC model. 2 So what were our recommendations? So what 3 we decided was that we could not be specific in terms 4 of what this joint review is going to look like 5 because FDA does not have its process completed yet. 6 However, we did decide that whatever joint process was 7 implemented, it had to meet the goals of the 407 8 process that was recommended and endorsed and adopted 9 by OHRP. So therefore it had to have all those goals 10 of transparency, expert input, public input, clarity, 11 consistency, et cetera. 12 In addition, we thought it very important 13 that as the FDA is determining its format, that OHRP 14 has the greatest flexibility to make decisions about 15 how it would implement some kind of a joint process. 16 We recommend that the joint adoption of the goals is 17 paramount, even when legal differences emerge. And 18 if, in fact, there are legal differences that make 19 either the process or recommendations somewhat 20 different, that this is made publicly explicit so that 21 it continues with transparency and public input. 22 Additional recommendations. One 23 possibility is, and we don't know, but one possibility 24 might be that if the FDA has a FAC, and OHRP has a 25 non-FAC open panel, that in some instances OHRP may 29 1 choose to ask the FDA FAC to review the protocol. If 2 that happens, then, once again, we would request from 3 the FDA, through OHRP, that the composition of the 4 committee reflect the kind of composition that OHRP 5 would be using on its own 407s, which means that maybe 6 experts would have to be invited to make sure that it 7 has the diversity and representation necessary and 8 sufficient for the diversity of protocols that are 9 coming in. 10 In addition, another priority for OHRP 11 that we would endorse would be that at least one 12 person who is the community representative would be 13 from a family. In addition, we did recognize that one 14 difference, if in fact it was an FDA fact, one 15 difference would be that we could not -- we, OHRP, or 16 the expert panel itself -- could not publish on the 17 website the independent expert opinions because there 18 would be none. And that would be something that would 19 be justifiable, there would be a consensus document, 20 and given that the meetings would be public, open to 21 the public and the public would have input, that that 22 would be okay. 23 Okay. This is the most complicated set of 24 issues and recommendations. And it was really kind of 25 fascinating to work on. The issue is what happens 30 1 when there are multi-site protocols, and one of the 2 sites asks for a 407 review, but the other sites 3 don't, or two sites do. Okay, so you can have 10 4 sites, and Mike Carome was really helpful in giving us 5 a number of scenarios what might happen. So one of 6 the things to keep in mind is that whenever you have 7 a multi-site study, each IRB independently judges the 8 nature of the protocol. And so the IRBs can differ in 9 their judgment of whether it's a 404, 405, 406, or 10 407. The funding is tied to each individual site 11 evaluation, which means that some sites who have 12 approved it already can start enrolling individuals 13 where perhaps another IRB hasn't even met yet. So 14 this is the complexity of the issue that faces OHRP. 15 Okay. So we had several hypotheticals. 16 But in general the hypothetical that we used to try to 17 think this is out was there are ten sites, nine of 18 them have approved the protocol on, let's say a 405, 19 which would be direct benefit. One site submits to 20 OHRP a request for a 407 review. At present, if OHRP 21 informs, let's say NIH and the PI, they may decide to 22 exclude the site and go on with their study. Now, 23 that was problematic for us on the subcommittee 24 because it meant that for multi-site studies, the 25 whole screening process that SACHRP had endorsed and 31 1 OHRP had endorsed would be different. It wouldn't be 2 there, and there wouldn't be the authority and 3 expertise that OHRP can offer applied to the study. 4 Other options that would happen was OHRP 5 could screen the application, and they could ask the 6 IRB to reconsider. OHRP might decide that, hey, this 7 is a 405, why don't you reconsider that. And the IRB 8 might agree, and they would move forward. 9 Alternatively, the IRB might not agree, and continue 10 to request the 407 review. That's probably a rare 11 possibility. Another option would be that OHRP would 12 say that there's sufficient data here to have a 407 13 review. It looks like a 407 might be reasonable. And 14 then the issue is who should decide and should 15 enrollments continue at the other sites that have 16 already approved the protocol. 17 Okay. What are our recommendations? So, 18 our recommendations are that OHRP should use the same 19 screening procedure for multi-site protocols that it 20 does for an independent 407 review. That is, if one 21 out of ten sites request a 407 review, OHRP should 22 screen it. They might request information from the 23 other sites to help them with their decision with 24 respect to feedback. And then as in the process 25 regularly, they would either give feedback that they 32 1 think that it's a 405 or whatever, or they would 2 determine that a 407 process should go on. We 3 recommend that it is not simply the decision of the PI 4 and the funding agency to decide to eliminate a site 5 if, in fact, OHRP determines that a 407 is legitimate, 6 or that it has responded. And that we believe that -- 7 I think I said that already, that it can seek 8 information. So we would like the authority to be 9 with OHRP in terms of moving the process ahead as it 10 sees fit. 11 Okay. OHRP should exercise its discretion 12 and authority to advise sites as to if it takes on a 13 protocol for 407 review, it should be OHRP's decision 14 to advise sites about whether or not enrollments that 15 may have started should be terminated, or enrollments 16 that they haven't started should not be initiated. Of 17 course, an IRB, it can always decide not to initiate 18 it. The final decision to suspend or terminate 19 enrollment for the entire study should rest with OHRP, 20 not with the funder or with the PI. Obviously we're 21 talking about the decision to terminate or not, if in 22 fact the IRBs have decided that it should continue. 23 And OHRP does have the authority under the FWA to do 24 this. And SACHRP should encourage NIH and other 25 funders to follow OHRP recommendations. 33 1 In addition, we recommend that OHRP have 2 the flexibility to determine whether or not suspension 3 or termination of enrollment should occur. This was 4 a very difficult issue because we recognize, we talked 5 about this a lot on the committee, sometimes it is in 6 a participant's best interest, perhaps, to terminate 7 a study, or suspend enrollment if, in fact, there is 8 an anticipation that there may be greater risk 9 involved than had initially been thought by the other 10 IRBs. At the same time, especially in clinical trials 11 research, it may not be in participant's best 12 interest, those who have already been enrolled, to be 13 pulled out of the study or to terminate it. Or it may 14 not be in the best interest of children to not have 15 additional enrollments. So we wanted OHRP to have the 16 flexibility to make those kinds of determinations. 17 What we wanted also to assist OHRP in some 18 kind of criteria that could be used in order to 19 determine whether or not enrollments should be 20 stopped. And here, of course, we are looking at the 21 risk-benefit ratio and whether or not there's a reason 22 to anticipate some kind of subject harm, or a lack of 23 -- unintentionally, but a lack of truly informed 24 consent because something has changed. So one of the 25 issues was whether or not a protocol that had been 34 1 judged to be a minor increase over minimal risk, a 2 406, in fact the 407 process was saying we think it's 3 greater risk than a minor increment over minimal risk. 4 So that would be a criteria which OHRP would consider 5 terminating a study. Now, once again, this is just 6 guidelines. But it's also helpful because it's not 7 pushing OHRP in an anticipation that enrollment should 8 always be stopped, but rather, just providing some 9 kind of a framework. 10 Second, another reason might be that the 11 other IRBs have approved something on the basis of a 12 405 that in fact it may have a great deal of risk but 13 potential direct benefit to the subject, and the 407 14 application is raising a question that there is no 15 benefit. So those would be the kind of two criteria 16 under which we provide support and guidance for OHRP. 17 I'm not sure we give guidance to OHRP, but helping 18 them with the criteria. 19 Okay. Now, the next issue is what do you 20 communicate to parents when there's a 407 review under 21 way and they're at a different site, and they've 22 already been enrolled in a study? And that also was 23 not a very easy decision, because if in fact it does 24 not -- sometimes a 407 review may mean that -- let's 25 say it's a 406, that the assessment is it's no more 35 1 than a minor increment over minimal risk, but the IRB 2 requesting the 407 review doesn't think there's a 3 condition. That's what would put it to a 407. So the 4 question is if in fact parents have been enrolled in 5 the study, would it also create additional anxiety to 6 let them know a 407 is in process if in fact a 7 reasonable person would not assume it would have 8 changed their informed consent. So those are the 9 kinds of things that we grappled with. 10 Now, if in fact OHRP determines that any 11 enrollment should be suspended, then the IRB should 12 determine the best way to tell the populations and the 13 parents about the termination. When OHRP determines 14 that enrollment should not be suspended pending 407 15 review, then the question is what should you inform 16 parents. So here we recommend that parents should be 17 informed that a 407 review is in process, if as I said 18 before there's a legitimate reason to assume their 19 consent decision might have been different if they had 20 been informed of this information. And kind of a 21 framework or criteria to use for that would be that a 22 designated protocol that parents were told had the 23 potential the direct benefit did not, or protocols to 24 which parents had been told were only a minor 25 increment over a minimal risk actually was suspected 36 1 of having greater risk. 2 Okay. If in fact -- what happens if the 3 secretary decides that the study should not be 4 approved after this one IRB put in something. What 5 does OHRP do, and what are families told? Now there 6 may be instances in which enrollment is permitted to 7 continue, but the risk-benefit calculus has 8 significantly changes. In that situation, we 9 recommend that parents give a re-consent. 10 Second, if enrollment is stopped, but it 11 may be that some participants need to continue because 12 they're being given treatment that is otherwise not 13 available, taking them off treatment would be 14 dangerous, then the guardians need to be informed of 15 these facts, that in fact they have the option of 16 continuing on the treatment, but that the study itself 17 has been terminated. If a child has completed 18 participation, is there any reason to notify the 19 parent that a 407 review, for example, is being 20 conducted, and the risk-benefit ratio either has been 21 changed or enrollment has been terminated. And we 22 recommend that that should only be done if in fact it 23 would affect the child's welfare, that the parent 24 would need to know something about the treatment, or 25 the situation the child was in, that might affect the 37 1 child's continued welfare. 2 Okay. Now, the next one is extending 407 3 review. At our last meeting in December -- I mean, or 4 whenever the subcommittee met, before the last 5 meeting, we had made this statement that the goals of 6 consistency, fairness, and participant protection can 7 only be fully achieved if the 407 process criteria 8 and/or purview are extended to all institutions that 9 have a federal-wide insurance, rather than simply 10 limiting it to those studies that are funded or 11 conducted by HHS, or regulated by the FDA. So at our 12 meeting, we discussed the feasibility of this. And 13 what we came up with was lots of limitations on doing 14 this. 15 First of all, institutions that hold a 16 multiple project assurance or an FWA are not obligated 17 to submit to OHRP for a 407 review of a project that 18 is not funded by HHS. And in addition, many -- we 19 don't know how many, but there certainly are 20 institutions that do not choose to come under that 21 kind of review for non-HHS supported research. OHRP 22 believes that existing statutes do not allow OHRP to 23 require that institutions apply their assurance to all 24 research. 25 In addition, if an IRB chose to submit a 38 1 407 that's not HHS-funded, it's not clear from the 2 regulations whether or not the secretary could even 3 make a decision about it. And requesting non-HHS 4 funded projects to conduct their own 407 review is 5 very complicated, and might discourage pediatric 6 research. Because remember one of the reasons we're 7 reviewing the whole 407 review process is because it 8 has been perceived as quite onerous on institutions, 9 or at least lacks clarity. Okay, so extending the 407 10 review recommendations. 11 One of the other things we realized that, 12 at least this is our view and our recommendation, is 13 that this is an issue for all types of research. It's 14 not just an issue for children's research. And so 15 simply to start the dialogue on pediatric research 16 really is probably not sufficient, and therefore we 17 would encourage OHRP to engage in dialogue with the 18 secretary and Congress about this very important 19 issue, but that it shouldn't be the focus at this time 20 of a children's subcommittee. 21 Another problem is that we suggest 22 caution, because unless the 407 process is 23 streamlined, there may be research that is not funded 24 by HHS, or not FDA-regulated, that if in fact there 25 are onerous regulations will shy away, as I said, from 39 1 research with children. But what we also realized was 2 that until there is clarity about 404, 405, 406, and 3 how it relates to 407, this is going to continue to be 4 a problem. Specifically we began to realize that this 5 gap between 406 and 407, what we do is in terms of 6 research that has no direct benefit, you go from a 7 minor increment over minimal risk to secretary 8 approval. And we really want to examine that to see 9 whether or not that is sufficient, or whether or not 10 there's a way to make some kind of a recommendation 11 that would perhaps better reflect the kinds of 12 decisions that IRBs have to make. 13 Now, our last one is monitoring the 407 14 process as SACHRP asked us to do, and OHRP is very 15 happy to do, is that OHRP should provide a yearly 16 report to SACHRP on 407 activities, and that the way 17 the report will read will be under the goals. So the 18 transparency -- so that SACHRP and OHRP can organize 19 its way of evaluating the 407 process, the new 20 process, in terms of the goals of transparency, public 21 input, harmonization, et cetera, et cetera. During 22 the year, OHRP should keep SACHRP informed about the 23 number of 407 applications. Sometimes it may be zero, 24 sometimes there may be a lot. And a SACHRP-designated 25 subcommittee. We are assuming it's the children's 40 1 subcommittee at this point, but this children's 2 subcommittee won't be around forever, and so a 3 designated subcommittee should work with OHRP on a 4 continual basis to monitor, and help work out, and 5 identify aspects of the new process that are 6 successful and those that are not. And the designated 7 subcommittee should issue an annual report and 8 recommendations, if necessary, to SACHRP. 9 So I think that's it. Okay, subcommittee 10 recommendations. All right, Susan, do you want to 11 take this? 12 MS. KORNETSKY: Okay, so what we want to 13 do, there's a lot of information, is really to go 14 through the different recommendations and have 15 discussion with SACHRP, the committee members, now. 16 And I think some of these will require more discussion 17 than others. And there was a lot of information. 18 So I think the first thing that we want to 19 just put on the floor for the members is our first 20 recommendation, which is picking up from where we were 21 last time is to really ask the group after thinking 22 about the different recommendations whether SACHRP 23 wants to endorse to OHRP that we use the non-FAC open 24 panel model for review that outlines the different 25 steps. And we had started some discussion, we sort of 41 1 did a straw poll at the last time coming back to it, 2 and we're opening, I guess, for discussion. So if 3 members want to bring up issues, points, 4 clarification, for Celia and myself. 5 CHAIR PRENTICE: Let's clarify the format, 6 Susan. I assume that what you want to do is present 7 each recommendation in turn. 8 MS. KORNETSKY: Yes. 9 CHAIR PRENTICE: Ask for a discussion of 10 that recommendation, and then try to bring it to a 11 vote if possible? Is that your plan? 12 MS. KORNETSKY: Yes. And if there are 13 things that are not ready to be voted upon, people 14 having concerns. There's a lot of information here. 15 I think Celia and I are willing to bring things back 16 to the subcommittee. I think some of these are maybe 17 a little bit easier than the others. 18 CHAIR PRENTICE: Okay. The way we'll run 19 this is when we have arrived at the time where we're 20 prepared to vote, if that time does occur, we'll 21 utilize the system where someone will make a motion, 22 and they will get a second, and then we'll ask for a 23 vote. 24 DR. FISHER: Maybe the condition, answer 25 after that lone response, that SACHRP had requested 42 1 that we provide a rationale for the open panel non-FAC 2 model. We are making -- the rationale that we are 3 using is that it's more timely, it is very difficult 4 for us to develop a report from our last meeting. 5 Trying to develop a criteria by which SACHRP would 6 decide whether or not it should send back information 7 or not expect a subcommittee review that's very 8 difficult. And whether or not SACHRP had the kind of 9 expertise that a panel would have is also a question 10 that we raised. The consensus document itself, as I 11 talked about before, the value of a consensus document 12 over public availability of independent expert reports 13 did not seem to be as salient as it was when we were 14 first discussing it. So we have provided SACHRP with 15 a rationale for why it would endorse a non-FAC open 16 panel model. 17 CHAIR PRENTICE: Celia, we need to record 18 everything here. So when -- Mark? 19 MR. BARNES: I just want to ask a 20 question. I'd just like to know how many 21 recommendations there are, and I wonder about whether 22 we should just see the sweep of the recommendations 23 before we -- and then go back and take them one by 24 one. But I would just personally like to see sort of 25 the list of recommendations, instead of seeing them in 43 1 isolation. 2 DR. FISHER: They're in your packet. At 3 the end, page 12. 4 CHAIR PRENTICE: Actually, Mark, the 5 recommendations have more or less been contained in 6 the presentation thus far. What Celia's doing is now 7 going back and presenting each recommendation in turn. 8 If you would prefer to have a quick overview of each 9 of the recommendations and then go back again, would 10 you like that? Okay. 11 MS. KORNETSKY: I think they're all here, 12 and we start with just -- I can summarize them quickly 13 without going through them. The first one is going to 14 be the actual model that we use. The second will be 15 the recommendation about the public member and how we 16 define that. The third recommendation will be about 17 harmonization between OHRP and FDA. The fourth will 18 be about multiple, which is rather complicated, the 19 multiple reviews. And that will include stuff such as 20 the screening, the communication to families. And 21 then the fifth will be extending the recommendations 22 outside of HHS, research our recommendations about 23 that. And then the last will be monitoring, the 24 sixth. So I think there are six recommendations. 25 DR. FISHER: Okay. So perhaps we should 44 1 go back to are there any questions. This stands by 2 itself. Are there any questions about the 3 recommendation for a non-FAC open panel model for 407 4 review? 5 CHAIR PRENTICE: Felix. 6 DR. GYI: As I look at this, I wonder if 7 there are differences in the models that impact on the 8 other recommendations. For instance, does choice of 9 a non-FAC vary how we communicate with the parents, or 10 how we try and harmonize? 11 DR. FISHER: None of that would differ in 12 terms of a family member, in terms of the 13 transparencies. In fact, it may allow OHRP to have 14 greater flexibility in harmonization if in fact the 15 FDA has an independent FAC committee looking at this. 16 So we did not see any benefits of either the 17 independent FAC or a subcommittee model in terms of 18 transparency, family input, and we did see an 19 advantage for timeliness and harmonization. 20 MS. KORNETSKY: Felix, I think in this 21 particular situation, thinking of the other five 22 recommendations, I can't see any except the advantage 23 that Celia brought up where if we decided to approve 24 this that there would be implications on the others. 25 I think all the others could follow, probably with any 45 1 of the models. So we may get into that with some of 2 the other recommendations, but this one I think really 3 wouldn't have implications on any of the other 4 recommendations. Unless you can think -- if you're 5 concerned about something, obviously please bring that 6 up. 7 DR. JONES: The other question I would 8 have is is this a standing committee? Would there be 9 a lot of flexibility? It seems if there's always a 10 family member that is familiar with whatever protocol 11 is being considered, there would be some shift-over 12 and also experts. But you also need some kind of 13 continuity, or, you know, the way that you apply 14 between a 405, 406, 407 would be lost if you had to 15 reconstruct. 16 DR. FISHER: In our last report, we had 17 recommended a standing pool that could be accumulated 18 by OHRP. But also the good thing about the open panel 19 model is that every 407 protocol is so different with 20 respect to the families and scientific expertise 21 that's needed that the standing pool would be 22 available, but also there would be this flexibility to 23 get the kind of expertise that's necessary. 24 CHAIR PRENTICE: Celia, what are your 25 thoughts about a chair for the committee? Like one 46 1 chair. I mean, I understand that you would add 2 members according to the nature of the research under 3 review, but having one individual who has an 4 appointment as the chair of this particular committee 5 for a reasonable period of time. 6 DR. FISHER: I would ask OHRP about that, 7 or you. I don't have a specific opinion about that. 8 CHAIR PRENTICE: I can give you my 9 feelings. I believe in having some consistency of 10 review, and having an individual who is qualified 11 appointed as chair for a period of time, like an IRB 12 chair. Maybe two years, maybe three years. I'd like 13 OHRP to comment on that. 14 EX. SECRETARY SCHWETZ: I don't think 15 there's one right way or other wrong ways of doing 16 this. But Ernie, I would accept what you say, but 17 perhaps add the possibility that you would at least 18 have alternate chairs available, designated, who have 19 had experience running these kinds of panels, so that 20 if you end up with somebody not being available for a 21 prolonged period of time it didn't hold up the 22 process. And that we would have a choice of two or 23 three chairs, and maybe one would be used for those 24 panels for which that person is available, but have 25 others who know they're in the queue so we have back- 47 1 ups. 2 DR. FISHER: So I'm not sure that we would 3 want to make that a SACHRP recommendation. I think 4 perhaps what we should do is use the monitoring 5 process to -- as OHRP experiments with respect to the 6 consistency of a chair, and then use that monitoring 7 process that we've put together to come back to SACHRP 8 and see how successful one approach versus the other 9 was in terms of a chair. 10 CHAIR PRENTICE: Other questions, 11 comments? Tom? 12 MR. ADAMS: When the committee looked at 13 the concept of how individuals would be selected to 14 participate, did you anticipate -- in the effort to be 15 transparent, as to how individuals are appointed. Did 16 you look at a process? 17 MS. KORNETSKY: Well, I think, I mean I 18 would again look to OHRP on how they've been doing it. 19 I think they are -- we didn't get into the specifics 20 in the process, and I think that's particularly 21 because each request is so different. But I think, 22 and perhaps Dr. Schwetz can talk about how they have 23 been appointed. I know that there are several people 24 who have served on several committees. Obviously, if 25 you look at our goals, expertise will be important. 48 1 We are adding something about a family member now. 2 You would want someone with ethics background. Dr. 3 Schwetz, I don't know if you want to comment a little 4 bit. I think there is a good process in place that 5 you have been using. And I'm not so sure that it has 6 to be an additional recommendation, but if you could 7 just clarify that for the group. 8 EX. SECRETARY SCHWETZ: In effect we have 9 a pool of people at this point. And it's not a formal 10 designation that's approved by somebody. It's a pool 11 of people whom we have had experience with who are 12 helpful in this process and are willing to do the 13 amount of homework that it takes to get it done 14 correctly. So we continue to use off that list of 15 people. But as protocols require subject-specific 16 experts, then we draw in people to add to this core 17 group who represent the components that we need to do 18 the review. And we add on an ad hoc basis, on a 19 further ad hoc basis, other experts. So little by 20 little, we have developed a list of people who are in 21 this pool of ones whom we would select from. And when 22 there is a report, we simply ask if they're willing to 23 help and if they're available and would serve on this 24 panel. 25 DR. FISHER: I'd also say that one of the 49 1 benefits of the newly adopted process is that the 2 identities, the background, and the expert opinion of 3 those individuals who are chosen will be available to 4 the public, will be on the web. So it's very -- from 5 what we understand from OHRP, if you really want to 6 meet the goals of timeliness, trying to get people to 7 agree to come and do these kinds of reviews is not 8 always easy. So a set process of identifying 9 individuals would be difficult. However, there 10 certainly would be public transparency about the 11 backgrounds and those particular persons' 12 recommendation so that the public can comment on that, 13 as can the IRBs themselves, or the PIs. 14 And I think that's also the beauty of the 15 monitoring process, because if in fact there are 16 public questions or public complaints about the 17 experts that are chosen, this is something that can 18 evolve over time. And actually it's very good 19 feedback. 20 CHAIR PRENTICE: Bob. 21 DR. HAUSER: Celia, would you remind me 22 about the function, how the open panel functions? My 23 recollection back in December was that the open panel 24 experts provide an opinion, but there is no 25 interaction between the open panel experts. Is that 50 1 still the case? And is this going to be resolved by 2 your -- 3 DR. FISHER: Right. The open panel model 4 that we're recommending must be a face-to-face public 5 meeting. So the experts meet together, all voice 6 their opinions. The public is present. In addition, 7 the public will have -- the announcement will have 8 been in the Federal Register, and all public comments 9 will have been submitted in time for the experts to 10 also be informed by public comments. So there will be 11 face-to-face interaction. The only difference will be 12 that it won't be one consensus document. Nor will 13 there be a consensus taken at the meeting, but rather 14 there will be a dialogue and exchange, and then 15 independent recommendations. And that would be an 16 improvement over the current process. 17 CHAIR PRENTICE: Bob, a clarification. 18 There's only been one non-face-to-face meeting 19 conducted. That was a joint review under FDA and 20 OHRP. That was for the pediatric Drivax vaccine 21 trial. All the other 407 reviews have occurred with 22 a face-to-face meeting, but obviously you're not 23 allowed to reach a consensus. But you do discuss the 24 protocol, and each individual produces an independent 25 report. FDA has not had any additional Subpart D 51 1 meetings since the pediatric Drivax vaccine. I assume 2 that's correct, David? 3 DR. LePAY: I believe that is correct, 4 yes. 5 CHAIR PRENTICE: Okay. So that was kind 6 of a change in what we have done in the past. 7 Comments? Okay, we have six recommendations we want 8 to try to get through. And we have about 35 minutes 9 before our break, and then another hour after that. 10 Are we able to move on this particular recommendation 11 yet? 12 MR. BARNES: Ernie, I'll make a motion to 13 accept this recommendation. 14 MR. ADAMS: Second. 15 CHAIR PRENTICE: Any further discussion? 16 All those in favor? 17 (Chorus of ayes.) 18 CHAIR PRENTICE: Any opposed? 19 (No response.) 20 CHAIR PRENTICE: Any abstentions? 21 (No response.) 22 CHAIR PRENTICE: The motion carries. We 23 will recommend that this model be adopted. Would you 24 move on to your next recommendation? 25 MS. KORNETSKY: Okay. So this is the 52 1 second recommendation with some advice for how we 2 think the public should be formally recognized on the 3 committee. Obviously, there's lots of input for the 4 public along the way, but actually as part of the 5 group. The recommendation is to appoint at least one 6 public member from a family of the specific population 7 to be involved in the research under consideration. 8 And again, I think it's important to 9 realize that we are recommending one, but also 10 recognize that in other situations it may be important 11 to have others, or other points of view. But again, 12 because of the timeliness aspect, felt that at a 13 minimum there should be one. And these are usually 14 not huge groups that are appointed. So I think we'll 15 entertain questions or comments about that. 16 CHAIR PRENTICE: Yes, Tom? 17 MR. ADAMS: I am assuming that for 18 purposes of discussion on this item, the additional 19 considerations are on the table at this point? Or are 20 you going to come back to that? 21 MS. KORNETSKY: If you want to put the 22 next slide up. Okay, so this would be tied into that. 23 Thank you, Tom. That there be at least one public 24 member, the recognition that in some cases community 25 representatives, in addition should be considered. 53 1 When the protocol does not include a specific disorder 2 or condition. And this specifically some of the 407s 3 come through because it involves normal children who 4 don't have a disorder or condition. So that's 5 specifically what that is geared towards. That it 6 should be a child advocate, we wanted to make sure 7 that there is someone who could speak to the 8 interests. Obviously we're looking here for the 9 interests of the population that has asked to be 10 included. And that individuals who can serve dual 11 roles, we thought it was important to separate that 12 out. So those are the four additional considerations 13 that are open for discussion as well. Thanks. 14 MR. ADAMS: The only one that I really had 15 a question about is the third one where we talk about 16 a child advocate. That begins to get somewhat murky 17 for me. I mean, there are all different types of 18 child advocates out there: clergy, social workers, 19 teachers, attorneys, judges. Did the committee take 20 a look at trying to define what we mean by `child 21 advocate'? 22 MS. KORNETSKY: No, we didn't. But if you 23 have some thoughts about that, how you think it should 24 be defined, or whether it should be limited at all, I 25 think we can discuss that. But no, we did not 54 1 specifically address that. 2 DR. FISHER: And the reason -- we did 3 discuss it, but the reason we didn't make a firm 4 recommendation about that is because of the 5 variability of the protocols. And so it might be -- 6 it's unclear what type of a child advocate would 7 always be the most appropriate advocate across diverse 8 protocols. But as Susan said, if there are issues in 9 terms of the narrowing of what that range might be, 10 clearly that would be helpful. 11 DR. HAUSER: Are we including the 12 additional considerations as part of the 13 recommendation? In other words, is this a -- the 14 first and the second slide recommendations and 15 additional considerations, is that all part of 16 Recommendation Number 2, if you will? 17 DR. FISHER: You know, I think you're 18 raising a really good point. I think that 3, if we 19 don't have 3 there, right? Because 3 is actually 20 saying that when the protocol does not include a 21 disorder, a family member, I think we have to clarify 22 whether or not it has to be a family member plus a 23 child advocate. I don't think that's clear. In other 24 words, is it a substitution or is it a family member? 25 MS. KORNETSKY: I think it has to be one 55 1 or the other. If you have a disorder or condition, 2 you'll be able to find a family member of someone who 3 has the disorder or condition. If you're involving 4 normal children, I think the idea is we really feel 5 it's important to have someone else substitute for the 6 interests of that population. So I think it has to be 7 at least one or the other. 8 DR. FISHER: So that would mean yes, 9 they'd have to be considered together. Susan, do you 10 want to? 11 MS. KORNETSKY: Susan was on our 12 subcommittee. 13 DR. WEINER: Can you clarify the question 14 again? There has to be at least one -- if the 15 disorder or condition is involved, then there has to 16 be at least one person representing that population. 17 That's the common denominator. And if it's normal 18 kids, then there has to be -- I mean, you know, it may 19 be the phrasing of this particular consideration -- 20 there has to be at least one person representing the 21 interests of that group. 22 DR. FISHER: So if it's a disorder or 23 condition it's a family member; if it's not a disorder 24 or condition, it's a child advocate. 25 DR. WEINER: I mean the problem may be 56 1 with the terminology. 2 DR. FISHER: Right. 3 DR. WEINER: There has to be one public 4 member who represents the interests of that 5 population. 6 DR. PRENTICE: Mark? 7 MR. BARNES: I want to comment on this 8 issue a little bit, because this is something that for 9 a couple of reasons I want to comment on it. One is 10 because this is not dissimilar to some of the 11 considerations that we've gone through on the Subpart 12 C committee in terms of trying to define who would be 13 an appropriate representative of the prison 14 population, or the incarcerated population, that would 15 likely become the subjects of a study, or could 16 potentially become the subjects of a study. But the 17 other reason I want to comment on it is because in my 18 previous roles in state and city government, this 19 issue of what kind of governance body or decision- 20 making body, what part of it should be composed of 21 people who are drawn from the populations who are 22 affected by the services, or the research, or whatever 23 the activity might be, was something that I and others 24 had grappled with extensively in the late `80s in 25 regard to HIV/AIDS and funding at the state and the 57 1 federal level for HIV/AIDS. 2 One of the -- and if I could just, just a 3 little history, so you can perhaps understand the 4 point. The state government in New York tried to 5 craft a series of enhanced Medicaid rates, Medicaid 6 reimbursement rates, for HIV/AIDS care really in order 7 to entice providers who were serving the Medicaid 8 population to come in and serve. And so we crafted, 9 when I was working for David Axelrod, the State Health 10 Commissioner then, we crafted a series of very 11 enhanced reimbursement rates. And so of course -- but 12 then the issue became these hospitals or these clinics 13 or community health centers, when they got access to 14 the rates, would they actually use the -- would they 15 design programs that would be user-friendly, or would 16 they simply be becoming Medicaid mills in order to 17 access the enhanced reimbursement rates. 18 And so we looked at requirements for 19 governance of these facilities, not simply community 20 advisory panels, but actually on the boards of 21 director or boards of trustees. And we had a debate 22 that really raged back and forth for about a year that 23 pitted AIDS advocates on the one hand against 24 representatives primarily of the Catholic church on 25 the other, because many of the Catholic facilities had 58 1 resisted having representation on their governing 2 bodies. And then the questions became sort of what do 3 you really want to achieve by having someone on the 4 governance body. And once you decide what it is that 5 you want to achieve, what is the best way to achieve 6 it. And I think this does have parallels here, which 7 is why I'm trying to give background. And just to 8 make a long story short, I mean what we ultimately 9 came to believe was not that we should actually say 10 that a person living with HIV or AIDS should be on the 11 board of trustees or board of directors, but instead 12 that the real purpose was to have someone who would 13 voice in an effective way, in a coherent way, the 14 interests of people who would be affected by the 15 program or facility. And so we tried to persuade, and 16 ultimately did I think, the AIDS advocates that there 17 should not be a kind of status test of the person who 18 would be the representative, but there should be a 19 kind of both ability and commitment test of the person 20 who would be the representative. 21 So the terminology that we ultimately came 22 up with was that there should be at least one 23 community representative on the governing board of the 24 facility, but that the test should be a person who is 25 self-identified with the interests of people that 59 1 would be served by the program or the facility. And 2 so that it would be a broad concept that would 3 encompass, for example, the mom or the dad of someone 4 who had died of AIDS, or someone who was living with 5 AIDS, or it could be a person who was a legal advocate 6 in a community legal services corporation who was 7 self-identified with the interests of the people who 8 would be served by the program. Anyway, the -- 9 DR. FISHER: Can I just ask? 10 MR. BARNES: Yes, sure, please. 11 DR. FISHER: Are you, and I think Susan 12 Weiner's going to have some comments. But just to 13 clarify, are you recommending -- are you speaking 14 about Point 3 here, or are you going back to -- 15 MR. BARNES: I'm going back to the overall 16 recommendation really. 17 DR. FISHER: Okay. So I just wanted to 18 clarify. 19 MR. BARNES: I'm not speaking just really 20 about the particular points. I think the points flow 21 from the general principle that you adopt here. So we 22 sort of had a recreation somewhat of this discussion 23 in regard to the -- at various points in our Subpart 24 C committee which we'll report on later today. And 25 ultimately, I mean just to kind of cut to the chase, 60 1 what we decided, or what we will likely recommend, 2 although none of our recommendations is really ready 3 for a formal recommendation to SACHRP yet, is that the 4 prison representative under Subpart C for the research 5 that is actually governed by Subpart C, which is 6 unfortunately a very small part of the universe of 7 prison research, just like you're having these similar 8 problems in regard to the jurisdiction of 407, is that 9 there should be one or more members who are self- 10 identified with the interests of persons who are 11 incarcerated, and who might become the subjects of the 12 research. So that it would not be that it would have 13 to be an ex-offender, not that it would have to be an 14 actual legal advocate, but it could be any or all of 15 those or none of those, but it really had to be a test 16 of self-identification with the interests. 17 So anyway, if we could just go back a 18 slide to the general recommendation. So, you know, in 19 this case, I actually think in practice, having this 20 recommendation would not be a problem because I really 21 can't imagine if you're talking about a narrowly -- it 22 would be hard to imagine a case in which the research 23 was targeted at a specific population of children that 24 was affected by a specific disorder, when a family 25 member of one of those children would not be self- 61 1 identified with the interests of those children. That 2 would be hard to conceive. But at the same time, I 3 think that it could well be that there could be others 4 who could be equally effective representatives. And 5 I just hesitate, actually, to have a kind of status of 6 a -- I hesitate to endorse a recommendation on which 7 the status of a representative is based upon his or 8 her actual membership in a population, as opposed to 9 their ability and willingness to identify with the 10 interests of the population. 11 DR. PRENTICE: Go ahead, Susan. 12 DR. WEINER: Okay. I understand the 13 principle, Mark, and agree with the principle. 14 However, this situation is not exactly analogous to 15 the prisoner case, or to the case that you mentioned 16 in New York State in that the family -- we're talking 17 about somebody signing a consent for someone else. 18 And so the experience of assuming that responsibility 19 is really vital. The experience of taking care of 20 someone whose disorder or condition might be the 21 requirement for a particular protocol I think is 22 essential. I think that many people -- that self- 23 identification is insufficient. And this doesn't 24 really say a parent. This says a family member. 25 So -- and I think that's a different 62 1 situation from a situation for normal kids where a 2 self-identified child advocate who was willing to 3 speak on behalf of children because of their 4 professional qualifications is a separate issue. So 5 I'm sorry. I don't entirely agree. 6 DR. PRENTICE: Let me suggest a couple 7 things here. In looking at the recommendation, and in 8 consideration of Susan's comments and Mark's comments, 9 and looking at additional considerations, in some 10 cases there is a bit of inconsistency, in my opinion, 11 between the way the recommendation is stated as 12 opposed to some of the additional considerations. So 13 specifically I think Number 3. 14 So how about this as a suggested 15 modification. Go back to the recommendation. There 16 you go. Each 407 review panel should appoint at least 17 one public member from a family of the specific 18 population to be involved in the research under 19 consideration, or other individual who can best voice 20 the interests of the population under study. Because 21 in some cases you are not going to have a population 22 that has a specific disease. They may have a 23 susceptibility to develop a disorder, but for the most 24 part they may be normal kids. So that would give you 25 more flexibility in terms of who is appointed. And in 63 1 effect it's OHRP that ultimately determines who is 2 going to be serving on these panels. Would that help 3 solve this problem? 4 DR. WEINER: I mean, only if you inserted 5 the phrase, "And in the case of normal children." The 6 more general after the disjunction, after "or." 7 DR. PRENTICE: Okay. 8 DR. FISHER: Right. I agree. But not 9 normal children, but in the case of research that's 10 not -- we could phrase it. I agree. 11 DR. WEINER: Research that doesn't involve 12 children with a disorder or condition. 13 DR. PRENTICE: Okay. 14 MS. KORNETSKY: Did that address Mark's? 15 No, it doesn't address Mark. 16 DR. WEINER: It doesn't address Mark's 17 issue. Mark is really talking about a general 18 principle which is of value. It's just that we're 19 talking about 407 cases with kids. 20 MR. BARNES: Actually it does address half 21 of my concern, because the other half of my concern is 22 about the third bullet point on the next slide. If 23 you could change to the next slide. And I was trying 24 to answer Tom's point about who in the world is a 25 child advocate. What do we mean by that. And so it 64 1 does address half of my point, not all of it, though. 2 DR. PRENTICE: Okay. I assume that we 3 agree in concept, obviously, with the public 4 representation. What we're doing is we are trying to 5 massage the terminology to get at how we can best 6 describe the necessary characteristics of such an 7 individual. Can we agree to move on this 8 recommendation, and then later on try to come up with 9 -- I think we agree in concept about the terminology. 10 We just have to -- if we try to editorialize here, 11 we're going to be here all day. We're not going to 12 get anywhere. 13 DR. WEINER: I have one more comment, 14 which is that I agree that that would be fine if the 15 re-crafted line which represents the elements we've 16 just discussed. But I would just like to make sure 17 that the fourth additional consideration is the second 18 part of that recommendation. So that it's clear that 19 there are distinct roles that members of that group 20 play. 21 DR. HAUSER: Could we just get the 22 recommendation that you stated as modified by Susan 23 written down? 24 DR. PRENTICE: I'm not quite sure. Susan, 25 would you go ahead and re-state? Okay, I said each 65 1 407 review panel should appoint at least one public 2 member from the family of the specific population to 3 be involved in the research under consideration, or 4 other individuals who can best voice the interests. 5 DR. WEINER: A family from the group. It 6 has to include disorder or condition in the first part 7 of the clause. 8 DR. FISHER: Can I just ask whether we 9 can't combine the two sentences? And then why don't 10 we do that. We start with this one, and then we just 11 add a second sentence, "when the protocol does not 12 include a specific disorder or condition, at least one 13 public member should be a child -- or should represent 14 the interests of the population studied." 15 DR. PRENTICE: Mark? 16 MR. BARNES: Let me try out a slightly 17 different approach, which is more consistent with the 18 principle that I tried to articulate, but which 19 perhaps will go so far as to incorporate Susan's 20 concern and assuage it. And that would be to have a 21 general statement that each 407 review panel should 22 appoint at least one public member who is self- 23 identified with the interests of children who would 24 likely become the subject of this research. And then 25 have a second sentence and say in the case of children 66 1 with a specific disorder or condition, the most 2 appropriate such representative would be drawn from 3 the family members of those who would be affected by - 4 - who are affected by the specific disorder or 5 condition. And then a third sentence. And actually 6 that's all you have to say, because then in the case 7 of children who are not affected by a specific 8 disorder or condition, the general principle takes 9 over. 10 DR. WEINER: But you basically shift it 11 from its being a requirement to its being a 12 suggestion. 13 MR. BARNES: No, not at all. No. 14 DR. WEINER: So let's take out the phrase 15 "when appropriate." 16 MR. BARNES: I'm sorry? 17 DR. WEINER: Let's take out the phrase 18 "when appropriate" so that it's clear that there's a 19 direct relationship between having a disorder or 20 condition and having the public member be from the 21 pool of people who have been affected by that. 22 MR. BARNES: Well, you know, there's still 23 a difficulty there, because one can imagine a 24 situation in which there could be children -- I mean, 25 I can't think of one. Actually, I can think of one, 67 1 but I think it's probably kind of an outlandish 2 hypothetical perhaps. But in which there are children 3 who would be with a specific disorder or condition or 4 status, who would actually not have family members to 5 represent them. And in that case, you can't have -- 6 there is no family member, which is why I think the 7 general principle should take hold rather than the 8 specific principle. 9 DR. WEINER: But if they're minors, they 10 have guardians, or they have the functional 11 equivalent. 12 MR. BARNES: Well, okay, but 13 institutionalized children, it may be that those who 14 are their official guardians are not those who are in 15 the best position to express their interests. 16 DR. WEINER: But there's got to be 17 somebody in loco parentis for those children. I mean, 18 you know, it depends on how specific you want to get. 19 DR. PRENTICE: Mary? 20 DR. POLAN: What is attractive, I think, 21 is Mark's going from the broadest statement of what is 22 important, and then honing down on just specific 23 individual situations. So I'm not so interested in 24 getting involved in the specific wording that Susan's 25 talking about. But I do think it's important to start 68 1 with the broad statement of how you want to approach 2 this, and then move to different specific situations. 3 So I like the way you introduce it. 4 I like the first sentence that gives -- 5 and I would also want to think about adding something 6 that says `an effective advocate.' So that you get 7 the concept of effectiveness, and efficacy in there. 8 Because one could also imagine a situation where you 9 had an advocate who was perhaps not the most effective 10 advocate for a whole variety of reasons. 11 DR. WEINER: Suppose we craft this over 12 the break, and then bring it to a vote afterwards? 13 DR. PRENTICE: I'll take one more comment, 14 and then I would endorse that suggestion. You guys 15 work out the language, okay? Don't take a break. 16 (Laughter) 17 DR. PRENTICE: Just work out the language, 18 then we'll come back. And we'll try to move on to the 19 next recommendation after Felix makes a comment. 20 DR. GYI: I would just ask you to remember 21 that I heard two different concepts being put on the 22 table. One is that of the role of the 407 panelists 23 who are looking at the science and the approvability 24 of the project. And the other is the role of a 25 representative in representing informed consent. 69 1 Because I heard that being stated as well very early 2 on, and then I sort of saw the discussion going in 3 that direction. So if you would, remember that we're 4 not looking at the point in time when subjects are 5 entering into the study at this particular juncture, 6 but rather whether it's approvable or not. 7 DR. FISHER: I think my bias is more with 8 Susan's bias, although I think there's a way to phrase 9 it. But I think one of the things that I think Susan 10 was saying, or maybe I took it as that, is that when 11 a child has a disorder or condition, a family member 12 is actually involved in the research. Whether that 13 family member is tested or not, that family member 14 brings the child, has to make the decision. So -- you 15 know, to the research. So I think that we -- there 16 is a special role for the most part, and I think the 17 issue of an exception when the family member is not 18 available is certainly a good one. And that we may 19 work out language. But I do think that in most 20 instances, parents do have a very unique position that 21 is different from an advocate simply for the child. 22 And I think that an advocate for the child may not be 23 able to fully represent the constellation of factors 24 that go into a child participating in research. So I 25 would continue to wade in the direction Susan wants 70 1 with modifications that have all the kind of caveats 2 that Mark was bringing up. 3 DR. PRENTICE: We're going to move on to 4 Recommendation Number 3. 5 MS. KORNETSKY: Okay, so this is the 6 recommendation about harmonization. And it really I 7 think what we struggled with was the issue that it's 8 very hard to recommend exactly how they're going to 9 harmonize when we don't know one side of the picture. 10 So these were really goals that should be kept in mind 11 in the harmonization. So I think what we're 12 recommending here is that in promoting this 13 harmonization, we want the goals of whatever group or 14 joint group is reviewing it to be the same. And 15 that's with input and timeliness, clarity, whatever. 16 That as FDA continues to develop its procedures, that 17 there should be some decisional flexibility to select 18 procedures to best meet the goals. That joint 19 adoption of these goals should be paramount, even when 20 legal authority differences result in different 21 reviews. In other words, to keep that goal of 22 harmonization right at the forefront, and possibly 23 trying to help even how FDA determines what its 24 process should be. And really that this needs to be 25 a priority. 71 1 I think there's another slide, now that 2 I'm looking. Could you go to the next slide? This is 3 additional harmonization requirements. Again, these 4 aren't real specific, but the membership should be 5 consistent with the SACHRP recommendations, which is 6 really just a statement on, again, the goals that we 7 want to accomplish. And that would be through the 8 membership. So that if we're making this decision, 9 whatever decision we do with a family member, however 10 it's worded, that that would also apply to FDA. 11 Recognizing some of the issues. I don't 12 think this is really a recommendation, but just 13 recognizing that there may be a difference in the 14 consensus document. However, even if that does 15 happen, we don't feel that the goals have been 16 jeopardized, because there are -- it will be open to 17 the public. And that the FDA process in developing 18 OHRP should have decisional flexibility to select 19 procedures to meet the best process. So really, 20 really I think the key point here is to -- whatever 21 process is used that there should be flexibility, and 22 that we should really -- the same goals should be kept 23 in mind. 24 DR. PRENTICE: Okay. I'd like to get some 25 clarifications from you, and possibly David as well. 72 1 What you're talking about there is when you have a 2 joint 407/50.54 review, and are you saying that it 3 could be conducted through the FDA FACA model, which 4 they're either going to have -- are they going to have 5 their pediatric advisory committee assume that 50.54 6 responsibility? 7 MS. KORNETSKY: This is part of -- I mean, 8 David can speak best to that, but we don't know for 9 sure yet. We don't know what that's going to look 10 like. This was a very hard recommendation to tackle 11 because we know nothing about one full side of the 12 picture and how it's going to work out. 13 I think what we're saying here is it seems 14 likely that that might be the goal, that might be what 15 they're going to do, and that in this situation I 16 think the underlying issue is that if whatever they 17 adopt is going to follow the same criteria and goals 18 that we've outlined, then it is possible that one side 19 could accept the other if they're both working under 20 the same goals. But David, why don't you address 21 that? 22 DR. LePAY: Some of these issues of course 23 are, as you mentioned, still under review at FDA. 24 Clearly we now have the ability to be able to develop 25 a full pediatric committee, which is new for FDA and 73 1 is based on recent legislation. That committee has 2 not yet been convened. So it is therefore difficult 3 to predict what the recommendations of that committee 4 will be. Clearly this will be a topic for that 5 committee to consider. We obviously have procedures 6 that are in place in the interim. We have had one 7 joint panel in the Drivax scenario, but I don't think 8 we anticipate that serving as the model for future 9 panels. 10 We are, again, asking some of these same 11 questions both within OHRP and at FDA to our legal 12 counsel to be sure that we have a full understanding 13 of how authorities will allow joint panels to operate. 14 But again, until we see the recommendations, until we 15 actually convene our full pediatrics committee and 16 have a chance to dialogue with that committee, I think 17 it's perhaps premature to put in place any lengthy 18 discussion of what the program will ultimately look 19 like. I think we anticipate that we will be operating 20 Subpart D through a subcommittee of that pediatrics 21 committee. But again, this is for deliberation by the 22 committee. 23 DR. FISHER: I want to clarify what our 24 recommendation is. I think we need to look at all 25 three recommendations at the same time. The 74 1 recommendation is that the membership should be 2 consistent with -- regarding expertise, continuity, 3 public and expert input. The FDA is committed to 4 public input, and so there's really no discrepancy 5 with what we're talking about in terms of the first 6 point. The second point recognizes the fact that if 7 in fact FDA does have a FAC, and OHRP chooses to 8 utilize that in a joint review, that the subcommittee 9 and if SACHRP endorses it, understands that the one 10 difference will be that independent expert panel 11 members' recommendations will not appear because there 12 will be none. And that we recognize that for the 13 purposes of harmonization, that that would be 14 acceptable. 15 The last point is probably most important, 16 is that at this point in time, since FDA has not 17 formalized what its procedure is going to be, that 18 OHRP has as much decisional flexibility that it needs 19 to best meet the process goals. And they may not meet 20 it perfectly at this point, and that's the beauty of 21 the continued monitoring and partnership with OHRP to 22 see how these joint reviews proceed. 23 DR. PRENTICE: Other questions, comments? 24 Felix. 25 DR. GYI: Of course, the complexity for 75 1 FDA-regulated studies, and the multi-site studies that 2 exist as opposed to a potential for a single site 3 review that 407 might fall under. In the first slide, 4 there is a statement about the FDA continuing to 5 develop procedures. I wonder if we might go back to 6 that. You started to mention a little bit about how 7 the communications might take place. Did you have any 8 further detail about how IRBs might reconcile that, 9 and how the communication might take place? 10 MS. KORNETSKY: No. I mean, it was very, 11 very hard, because we don't even have the specifics of 12 how the committees are going to operate. I mean, I 13 think we need to understand how they will operate 14 before we can guide IRBs on how that communication -- 15 I mean, it's definitely a very important issue, Felix. 16 And I don't think we can get to that point without 17 sort of understanding the mechanics of a joint review 18 or whatever. 19 DR. FISHER: I think the most important 20 issue for the subcommittee was that we do not abandon 21 the goals that were endorsed by SACHRP, and adopted by 22 OHRP when there is a joint review. And I think that's 23 -- but the details and the mechanics of the process 24 are impossible to make a recommendation about because 25 we don't know what FDA is going to be doing. 76 1 DR. PRENTICE: Yes, Tom. 2 MR. ADAMS: When I look at this, it would 3 seem to me that maybe what an option might be to adopt 4 the first goal, and then add additional language 5 suggesting that at the point in time that the FDA's 6 regulations are developed, that we come back and 7 revisit it. 8 MS. KORNETSKY: I think the important 9 point here is we want to do what we can to prohibit 10 two different types of processes. Because then that's 11 going to help neither side, and it's not going to help 12 the goals on either side as well. So I agree, that's 13 what we, you know, we want to make a statement, we 14 want a very strong statement, that says whatever is 15 done, these things have to be taken into 16 consideration. And have an input, a potential input 17 so that as FDA deliberates, they know that, and agree 18 to that hopefully. 19 DR. PRENTICE: David? 20 DR. LePAY: Just to add a few comments 21 here. I did have the fortune of being an ex officio 22 member to the subcommittee, and therefore had a chance 23 to also discuss some of these goals as they were being 24 developed, and felt these were certainly very 25 compatible with what we would see as a process as it 77 1 develops within FDA. So I didn't see any particular 2 difficulty in being able, from an FDA perspective, to 3 adopt the overall goals, the overarching goals. 4 Secondly, we do have a focal point within 5 FDA, FDA's new Office of Pediatric Therapeutics, which 6 is a focal point within the agency for IRBs if indeed 7 there are requests to FDA either for a panel under 8 50.54 or in a joint panel. So there is a 9 communication pathway available that should in fact be 10 known to the IRB community, and is available if there 11 is the potential for such a panel to be convened 12 within FDA. 13 And in terms of the direction, I certainly 14 cannot answer for the ultimate direction that we will 15 take in turn. But as I say, our expectation is having 16 a full pediatric committee. We will develop some 17 structure off of that pediatric committee, which of 18 course makes it a full FAC committee, to be able to 19 handle these panels within FDA as single panels or as 20 joint panels. And as we've discussed with the 21 subcommittee, we believe that the model that's being 22 proposed here, at least to the extent that we 23 understand it now, and our legal discussions of it, 24 could be compatible with what we are envisioning for 25 FDA, even though we can certainly not commit to that 78 1 until we've actually convened a full pediatric 2 committee. 3 MS. KORNETSKY: David, is there a timeline 4 for deciding? I mean, the FDA has adopted these 5 guidelines for a while. Is there any timeline for 6 when you're going to decide how you're going to deal 7 with this? 8 DR. LePAY: Well, it hasn't been all that 9 long, because of course one of the issues has been -- 10 this is the ability to have a pediatric committee was 11 only permitted through legislation. And with that 12 legislation, there were not clear considerations for 13 how this would be funded and operational. This has 14 now been put into place with the new budget. So of 15 course now we can start talking about as some 16 concrete, finite entity. 17 I can't give you a date or a timeline. I 18 know we've been actively discussing it even within the 19 past few weeks. So again, it takes awhile, of course, 20 to get the mechanics in place for any advisory 21 committee, but hopefully not all that long. 22 DR. FISHER: I just want to say that if we 23 go with Tom's recommendation, I do think giving -- it 24 can't stand by itself, that we must give OHRP the 25 flexibility to do it in the best way possible. And so 79 1 I would, you know, if we go to the other slide, I 2 would -- yes. I would definitely keep in Number 3, 3 because we don't want SACHRP to adopt and say you 4 must, you must, you must, and it's impossible this 5 year to do that. I think the monitoring will also 6 help to see whether -- the extent to which meeting all 7 those goals are positive. So I would just amend that 8 to Tom's recommendation. 9 DR. WEINER: I guess I would also. I 10 think it's very important that we include the last 11 bullet. That is, that we state explicitly that this 12 is a priority. 13 DR. PRENTICE: Okay. So, are we ready to 14 move on this recommendation? All right. Would 15 someone like to make a motion? 16 MR. ADAMS: I move approval. 17 DR. PRENTICE: Well, we need to clarify 18 exactly what the recommendation is. So? 19 MR. ADAMS: I would move that we take 20 Point 1 and Point 6?\. And Point 6 as the 21 recommendation. 22 DR. PRENTICE: All right. Let's make sure 23 we're clear on that. That Point Number 1 is the goals 24 of transparency, public input, expert input, et 25 cetera, must be at the forefront of any joint review 80 1 process. That's Number 1. And you said, all right, 2 Number 6 would be as the FDA processes developing, 3 OHRP should have decisional flexibility. That's fine 4 because we may have a joint review in the next year or 5 so where we've got to have some flexibility. So 6 that's fine. So those two. What else? 7 MS. KORNETSKY: I think that really takes 8 care. I mean, if we do those two things, I think 9 these other things really fall in place. It's just 10 sort of restating some of the initial issues and 11 goals. 12 DR. PRENTICE: I think you can also say 13 that where and whenever possible, harmonization of the 14 process should be a priority. That does not change or 15 alter the flexibility. So that's what? That's -- 16 okay. Does everybody agree with those? 17 DR. HAUSER: So, joint adoption of these 18 goals should be paramount, we are not including that? 19 Is that correct? 20 DR. PRENTICE: I think you wanted that 21 Susan? 22 DR. WEINER: No, no. I just wanted the 23 last one that you stated. 24 DR. PRENTICE: Okay. 25 DR. WEINER: That is Point 4 on that top 81 1 slide. 2 DR. PRENTICE: All right. 3 MS. KORNETSKY: I don't think that's 4 absolutely necessary. I mean, I think that that's 5 covered, and if we adopt -- if we take the other 6 three, I think that's within that. 7 DR. PRENTICE: So we've got four 8 altogether. All right, is there a second? Four? 9 Three? There's still three? Yes, you're right, 10 because there's a repeat on the next slide. There's 11 three. So do we have a second? 12 DR. WEINER: I second. 13 DR. PRENTICE: All right. Any further 14 discussion? Those in favor? 15 (Chorus of ayes) 16 DR. PRENTICE: Any opposed? 17 (No response) 18 DR. PRENTICE: Any abstentions? 19 (No response) 20 DR. PRENTICE: Okay. Motion carries. We 21 will now take a 15-minute break. We'll reconvene 22 exactly at 10 to 11:00 and continue. 23 (Whereupon, the foregoing matter went off 24 the record at 10:32 a.m. and went back on the record 25 at 10:53 a.m.) 82 1 CHAIRMAN PRENTICE: On the record. Okay, 2 during the break a public member recommendation was 3 crafted based upon the discussion. We want to move 4 into that now. But before we do so, I would like to 5 inform you that Dr. Schwetz regrets that he has to 6 leave for a short period of time at 11:00 a.m. 7 However, I think that you will agree that it's 8 important that he attend. 9 This is the announcement of the 2004 World 10 Food Prize Laureate which is going to be presented by 11 Colin Powell and Venneman, the Secretary of 12 Agriculture. So it's quite an honor to be invited to 13 go to this award ceremony, Bern. We will miss you but 14 we understand why you have to leave. 15 All right, this is the new language. 16 Celia or Susan, would you like to go over it very 17 briefly, indicate what might be different about it, 18 and anything else you want to say. 19 MEMBER KORNETSKY: Susan is here. Mark is 20 not here, but all four of us have agreed to this. 21 We're starting here saying each 407 review should 22 appoint at least one public member who is identified 23 as an effective advocate for the interest of children 24 who would likely become subjects of the research and 25 is himself identified with those interests. So I 83 1 think that's starting out with the overall principle 2 that Mark clearly brought up. 3 We go on to say that in the case of 4 children with a specific, defined disorder condition, 5 a family member or guardian of such child should be 6 appointed as his public member. So that's bringing in 7 the concept when we have a disorder condition the 8 discussion that Susan brought up and felt strongly 9 about that it should actually be a family member for 10 all of the reasons that Susan brought up with 11 decision-making and what it is to live and have a 12 child with that type of disorder condition. 13 The last point is if there is no such 14 family member or guardian - this would be in the case 15 of normal children - to voice the interest of children 16 so affected, a child advocate should be appointed. 17 Oh, it wouldn't be normal. It's not normal. If there 18 is no family member or guardian to voice the interests 19 of children so affected, a child advocate would be 20 appointed. I'm sorry. 21 MEMBER WEINER: What is confusing about 22 that is that you don't need the third bullet. 23 MEMBER KORNETSKY: If there is no such 24 family member or guardian to voice the interest of the 25 child, a child advocate should be appointed. That's 84 1 correct. 2 CHAIRMAN PRENTICE: All right, open for 3 comments or questions. 4 MEMBER ADAMS: I would concur with Susan. 5 It looks to me like in the event of number three, if 6 it were to occur,