1 UNITED STATES OF AMERICA + + + + + DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION + + + + + MEETING + + + + + TUESDAY MARCH 14, 2006 The Advisory Committee met in the Jefferson Ballroom in the Radisson Hotel, Old Town Alexandria, 901 North Fairfax Street, Alexandria, Virginia, at 8:30 a.m., Ernest Prentice, Ph.D., Chairman, presiding. MEMBERS PRESENT: ERNEST D. PRENTICE, Ph.D., Chairperson BERNARD A. SCHWETZ, D.V.M., Ph.D., Executive Secretary CATHERINE SLATINSHEK, M.A., Executive Director CELIA B. FISHER, Ph.D., Member NANCY L. JONES, Ph.D., Member FELIX A. KHIN-MUANG-GYI, Pharm. D., Member SUSAN KORNETSKY, M.P.H., Member NEIL R. POWE, M.D., M.P.H., M.B.A., Member JAMES H. POWELL, M.D., Member ADA SUE SELWITZ, M.A., Member 2 EX OFFICIO MEMBERS PRESENT: PEG BARRATT, Ph.D. KATHRYN LYNN CATES, M.D. PATTY DECOT SALLY FLANZER, Ph.D. DAVID A. LEPAY, M.D. AMY PATTERSON LAWRENCE UHTEG ALSO PRESENT: KELLY BOOHER KRISTINA BOOROR MICHAEL CAROME JULIA GOREY SHIRLEY HICKS IVOR PRITCHARD IRENE STITH-COLEMAN 3 C-O-N-T-E-N-T-S PAGE Welcome and Opening Remarks . . . . . . . . . . . .4 Report of Subcommittee on Research Involving Children . . . . . . . . . . . .5 Public Comment. . . . . . . . . . . . . . . . . .153 Panel on Status of Research Ethics/Training Internationally . . . . . . . . .167 General Discussion. . . . . . . . . . . . . . . .259 Wrap-up and Adjourn . . . . . . . . . . . . . . .302 4 1 P-R-O-C-E-E-D-I-N-G-S 2 (8:38 a.m.) 3 CHAIR PRENTICE: Welcome to the second day 4 of SACHRP's March meeting. 5 As is customary, I will overview the 6 agenda for today. We're going to begin at, as soon as 7 I get done, about 8:40 with the report on the 8 subcommittee research involving children, co-chaired 9 by Celia Fisher and Susan Kornetsky, we'll take a 10 brief break, then we'll come back and continue with 11 that particular report. We'll break for lunch around 12 12:00. We'll have a public comment period between 13 1:00 and 1:30. And then between 1:30 and 4:30 we have 14 a panel on the status of research ethics training on 15 the international setting. And in this particular 16 panel, we're going to deviate from our normal 17 procedure in that I'm not going to be the kind of like 18 the moderator or the facilitator. We've asked Bob 19 Levine to perform that particular role. So, in 20 addition to actually presenting, he will serve as the 21 moderator. 22 And, you can see that we have a 5 1 distinguished number of panelists who will talk about 2 various aspects of research ethics training on the 3 international setting. Melody Lin, David LePay, Jean- 4 Louis Saillot, Maureen Power, Karen Hansen will 5 actually not be talking initially in terms of 6 presentation but she will come up and sit at the table 7 when we engage in a discussion, and Barbara Sina. 8 Then we're going to wrap up at 4:30 and adjourn. 9 I want to remind everybody of our future 10 meeting dates, they're already set. The next meeting 11 will be July 31st and August 1st of 2006 followed by 12 our November meeting November 2nd and November 3rd, 13 2006. So, I would encourage all of you to place those 14 dates on your calendars. 15 All right. I think we had a very 16 productive day yesterday and I'm looking forward to 17 duplicating the productivity today with our children's 18 research subcommittee's report. So, if Celia and 19 Susan would assemble presumably up here, and we can 20 get started. 21 MEMBER FISHER: Okay. It's on? Hello. 22 Today we are going to divide our 6 1 presentation in to three parts. The first part we're 2 going to talk about issues of parent permission and 3 child assent. Then we're going to move on to 405 4 issues in terms of research, providing direct, the 5 potential for direct benefit and then we're going to 6 move on to the issue of 409 and wards. And we'll 7 separate that out so that it's clear and SACHRP can 8 deliberate in segments. 9 As you know, we have an incredible 10 committee, subcommittee, as well as actually wonderful 11 ex officios who contribute a great deal to our 12 deliberations and, of course, a wonderful OHRP staff. 13 So the meeting goals of our last meeting 14 were to review waiver of parental permission and the 15 revisions suggested by SACHRP to revisit issues 16 relevant to 405 and to examine wards of the state. 17 Now, as you will recall, at our last meeting, there 18 were a lot of recommendations on parental permission 19 and child assent that were approved by SACHRP. So we 20 have that at the end of the parent permission, child 21 assent section, if you want to reference those in the 22 power point, but we're not going to go over those. 7 1 What we are going to go over are the 2 particular recommendations or issues that SACHRP asked 3 us to take back and reconsider and which we did. We 4 have proposals and we've tried to highlight the issues 5 just to remind SACHRP on the issues that they were 6 concerned about. 7 So, just as a reminder, when we're looking 8 at parental permission and child assent, there are two 9 regulations that we can look at. The first is in 10 subpart A 116(d) which permits waiver of consent for 11 minimal risk research and then there's subpart A 408 12 which permits waiver of informed consent, being in 13 this instance parental permission for child assent, 14 across all types of risks. So, we will be making 15 those distinctions and have made those distinctions. 16 So, to remind you, 46.116(d) permits 17 waiver of informed consent if the research involves no 18 more than minimal risk, if the waiver or alteration 19 will not adversely affect the rights and welfare of 20 the subjects, the research could not practicably be 21 carried out without the waiver, and where appropriate, 22 the subjects are provided with additional pertinent 8 1 information. The issue that we attempted to address 2 was helping to clarify, and some potential guidance, 3 what adversely affect the rights and welfare of 4 subjects might mean and how a decision-making tree 5 might be helpful to IRBs and investigators in terms of 6 attempting to decide on whether or not there's an 7 adverse affect. 8 So, the first requirement and, once again, 9 when I say requirement I don't mean that this would be 10 guidance if accepted so these are points for 11 consideration that would have to be, that the IRB 12 would want to be met. So, the first would be a 13 consideration of federal, state, or local laws 14 pertaining to parent-guardian permission. 15 The second would be alternate mechanisms 16 to protect the rights and welfare of child 17 participants and it's the third bullet that we had a 18 great deal of discussion on at the last SACHRP meeting 19 in terms of what we mean by a community and whether we 20 wanted to have some sort of community advice within 21 the guidance itself. 22 And so, based on SACHRP's discussion, we 9 1 altered the language that you see in green to when 2 appropriate, whether the investigator has adequately 3 considered the norms of the community from which 4 subjects will be drawn. And, as you can see, we added 5 when appropriate to give the flexibility that that 6 might be necessary in order not to be in some sense 7 dictating community advice or equal rights or those 8 kinds of issues. 9 Examples of relevant laws, the first 10 bullet, would by HIPAA, for example, PPRA or FERPA are 11 the kinds of laws, if you're working with children in 12 a minimal risk study and thinking about waiving 13 parental permission, you'd have to consider those 14 types of laws most likely. Alternate mechanisms, for 15 example, the investigator is provided adequate 16 procedural protections to ensure the child subject's 17 assent to participate will be informed and voluntary 18 or there might be an independent participant advocate, 19 depending upon the needs and the population. 20 An example of how one would meet the local 21 norm recommendation would be the investigator has 22 provided a reasonable argument that the waiver would 10 1 not adversely affect the parent-child relationship 2 within the community from which the subjects will be 3 recruited or community prospectives have been actively 4 sought. There might be an unaffiliated nonscientific 5 IRB member who knows the community that might be able 6 to speak with them, or there might be consultants. 7 To give an example of studies that could 8 be approved under that type of guidance to determine 9 whether food intake patterns match, census track 10 patterns of obesity, a PI requests a parent-guardian 11 permission waiver to administer a survey on soft drink 12 and fast food intake to 2,000 middle school students 13 in different socioeconomic communities and is applying 14 to the IRB to waive parental permission. It's a 15 minimal risk study. There are no laws that require 16 parent permission for questions about nutrition, the 17 investigator has worked with the local PTA in 18 developing the procedures, and middle school children 19 are old enough to understand the assent information, 20 and arrangements were made with school personnel to 21 make sure that participation was voluntary. So, this 22 would meet all three considerations, the law, adequate 11 1 protection, as well as community norms considered. 2 An example where parental permission might 3 not be waived, even though its minimal risk was, for 4 the same fast food study, the investigator also 5 proposes to correlate eating patterns with middle 6 student grade point averages. FERPA does not permit 7 the school. So, in terms of the law requirement, 8 without parental permission the investigator should 9 not have access to the children's grades or school 10 records. In this particular community, there is an 11 Orthodox Jewish group that would be concerned that 12 questions about pork might be contrary to their 13 religious teachings and send a message. Without 14 consultation to that community, it would probably be 15 wise to the IRB to at least ask for that kind of 16 feedback giving parents rights to decide their child 17 should not be in the study. 18 And the appropriate mechanism was the 19 investigators wish to conduct the fast food study with 20 preschoolers, it's hard to -- of course, that's not a 21 very good example, because they're not going to have 22 a grade -- let's say first grade instead of -- I don't 12 1 know why I put in preschoolers, but they could not 2 assent and the voluntary nature would be somewhat 3 questionable. 4 Okay. The next issue is what does good 5 practicably be carried out without a waiver mean? 6 What does that term practicably mean? So, our 7 recommendation was modified. One of the reasons this 8 was modified was that we had several recommendations 9 that we difficult to put together so we tried to 10 collapse it to make this a little more understandable 11 and cohesive. So, the recommendation is to determine 12 whether parent permission can be waived under 13 116(d)(3) because the research cannot be practicably 14 carried out, the IRB should require investigators to 15 provide a reasonable argument that scientific validity 16 would be compromised if parental permission was 17 required. So, we're defining practicably in terms of 18 the science and the scientific validity, a rationale 19 for why the research could not be conducted with a 20 population for whom parental permission could be 21 practicably carried out. And so, it's not sufficient 22 to say, oh the parents aren't home, so it's hard to 13 1 get their parental permission, for example. And a 2 reasonable argument that alternative methods to obtain 3 parent-guardian permission are not feasible. And 4 instead of having a separate -- as you can see the 5 asterisk sentence, that was a separate recommendation, 6 we've not asterisked this recommendation to underscore 7 the fact that guardian permission should not be waived 8 for convenience nor waived solely for reasons of cost 9 or speed or other expedient measures, if doing so 10 weakens protection of subjects' rights and welfare. 11 An example of parent permission that could 12 be waived under this recommendation would be PI 13 proposes to waive parental permission for a national 14 study of diet and after school activities to predict 15 census track concentrations of middle school 16 children's respiratory disease. Remember these are 17 minimal risk studies. Scientific validity 18 requirement, a large sample of children is necessary 19 for statistical power. Alternative methods, the 20 census track neighborhoods vary with respect to 21 ability to contact parents through telephone directory 22 or other measures, so it would not be evenly spread 14 1 out across the census tracks. Alternative 2 populations, all census tracks must be included for 3 the data to be meaningful. So, that would satisfy the 4 criteria. 5 So, those are the two standards that we 6 revised -- not standards, I'm sorry, guidance 7 recommendations that we revised for 116 and now we're 8 going to go to 408. 9 Once again, to highlight the distinctions 10 between 116 and 408, well, 116 criteria are limited to 11 minimal risk. 408 criteria applied to minimal as well 12 as greater than minimal risk research. For minimal 13 risk research, the IRB approval of waiver under 116(d) 14 is sufficient. However, minimal risk research -- what 15 that means is is that we are suggesting, we believe in 16 our interpretation, that an IRB does not have to go to 17 408 or anything in the 4s in order to waive parental 18 permission, if it's minimal risk research and 19 satisfies the guidance. That 116 would be sufficient 20 because it's -- However, minimal risk research that 21 does not meet parent-guardian waiver under 116(d) may 22 meet waiver requirement under 408(c) because 408(c) 15 1 addresses harm posed by parent-guardian permission 2 itself. So, what might not be able to be approved 3 under 116 might be able to be approved as a waiver 4 under 408. 5 So, in addition, this is just a 408 6 regulations in addition to the provisions for waiver 7 contained in 116, if the IRB determines that a 8 research protocol is designed for conditions or for a 9 subject population for which parent or guardian 10 permission is not a reasonable requirement to protect 11 the subjects, for example, neglected or abused 12 children, so we are going to be addressing what that 13 language means, not a reasonable requirement. It may 14 waive the consent requirements in subpart A of this 15 part and paragraph of this section provided an 16 appropriate mechanism for protecting the children will 17 be in place and that it's not inconsistent with 18 federal, state or local law. 19 The choice of an appropriate mechanism 20 would depend upon the nature and purpose of the 21 activities described in the protocol, the risks, 22 etcetera. 16 1 Okay. So, the question we were trying to 2 address was, outside of neglect or abuse, when can 3 parental permission be waived under the term 4 reasonable requirement to protect the subjects? 5 Something that we brought up last time was that many 6 IRBs are reluctant to approve anything other than 7 abuse and neglect because abuse and neglect is within 8 the federal regulations, even as examples. So, they 9 kind of limit themselves to the example rather than to 10 the spirit of the language. 11 So, our third recommendation is how do you 12 interpret not a reasonable requirement? First, in 13 considering parent-guardian waiver under 408(c), IRBs 14 should consider justifications for not a reasonable 15 requirement beyond the example of neglected and abused 16 children given within the regulation and include 17 instances in which parent-guardian permission would 18 jeopardize subject welfare or fail to provide 19 additional subject protections. 20 Now, what would that be? And this was 21 also modified on the basis of SACHRP recommendations. 22 Assuming that an appropriate mechanism for protecting 17 1 the children is provided, the IRB may waive parent- 2 guardian permission under 408(c) applying the 3 following three criteria. And it was these first two 4 criteria that SACHRP had a lot of discussion about. 5 So these are the ones that have been modified. 6 The investigator has provided a reasonable 7 argument that informing parents may result in harm to 8 the child or the investigator has provided a 9 reasonable argument that parent permission may not be 10 in the child's best interest because of conflicts in 11 the parental role as it relates to the research; 12 that's what we had a great deal of discussion about at 13 the last SACHRP meeting, to make sure that we are not 14 having some kind of statement or guidance that the 15 parents are not good parents, but rather that, for 16 this particular research situation, there may be a 17 conflict in role interests. And we'll give some 18 examples to explain what that is. 19 So, and then the third requirement was, 20 and this had come from the IOM recommendations and had 21 not been controversial at our last SACHRP meeting, the 22 research involves adolescents and satisfies all of the 18 1 following. The research is important to the health 2 and well-being of the subject population, the PI made 3 a reasonable argument that the subject population is 4 capable of understanding the research and their 5 research rights, adequate protections are in place to 6 assure the voluntary nature of participation, and the 7 research involves experiences or procedures that are 8 reasonably commensurate with those inherent in- 9 treatment that state laws permit adolescents to 10 receive without parent-guardian permission. As you 11 will recall, many laws have emancipated minor -- many 12 states have emancipated minor laws that are silent 13 about research. And so, investigators and IRBs are 14 confused if someone is, if an adolescent is permitted 15 by law to have a particular medical or psychological 16 procedure without parental permission, are they 17 permitted to be asked about that procedure without 18 parental permission? So, here they've done IOM and a 19 number of other, NHRPAC, we are recommending that that 20 law should provide guidance. 21 Not a reasonable requirement, example one. 22 The investigator -- and so, this is criteria one. 19 1 Criteria one is that the investigator has offered a 2 credible argument that physical, social or 3 psychological harm may come to the child subjects if 4 parent-guardians are informed about the reason for the 5 study. The example is a PI who seeks to identify 6 patterns of psychological risk and resilience in high 7 school students who consider themselves gay or lesbian 8 but have not made this identity public. 9 Now remember, this is not intuitive. We 10 are requiring that the investigator has offered a 11 credible argument. So, that might be literature on 12 the social stigmatization of, in this situation, gay 13 or lesbian youth, their potential confusion, whether 14 or not there is evidence of abusive reactions in 15 particular populations. So, it's the investigator's 16 responsibility to provide a credible argument. 17 The second requirement would be the 18 investigator has offered a credible argument the 19 parent-guardian may not make permission decisions that 20 are in the best interest of the child because of a 21 role conflict related to the specific study. An 22 example might be that a PI seeks to study coping 20 1 behaviors of adolescents who have joined an Al-Anon 2 group. By definition, let's say there's only a single 3 parent, that parent is an alcoholic. There might be 4 a conflict between permitting that type of study and 5 the concerns of the parent that are not necessarily 6 evaluating the best interests of the child, but only 7 in that particular situation for that particular type 8 of research. 9 Not a reasonable requirement, example 10 three, this is the adolescent requirement. The PI 11 applies for a parental waiver to study adolescent 12 girls' attitudes towards and use of different forms of 13 birth control. Participants will be recruited from a 14 clinic serving teenage girls 14 years and older who 15 are permitted by state law to receive gynecological 16 services and birth control without parental 17 permission, and the subjects are adolescents, and the 18 research is important to the health and well-being of 19 adolescent females who are sexually active. 20 The investigator has provided empirical 21 evidence demonstrating that adolescents of this age 22 are capable of understanding informed consent at adult 21 1 levels. You may remember last time we put in 2 literature suggests 14 and over and there was some 3 concern about that, but guidance should not be 4 dictating an age that may change with empirical 5 evidence. 6 The PI has assured that during recruitment 7 it is clear to the teenagers that participation in the 8 study is not related to their treatment and a decision 9 not to participate will not jeopardize their ability 10 to get services. So the voluntary nature of consent 11 is assured. And asking subjects about their sexual 12 practices and use of birth control is reasonably 13 commensurate with questions as during gynecological 14 services that they are permitted by law to receive 15 without parental permission. So, it is very much in 16 keeping with the procedures that are approved by law 17 for the adolescents to receive. 18 And then the final change, which is not 19 really a change, it is a removal. As you will recall, 20 there was part of the emergency recommendation that 21 said that parental consent could be waived even when 22 the parents were there and we had feedback from FDA as 22 1 well as from the committee, so we withdrew that 2 recommendation. 3 And the rest of the recommendations have 4 already been approved. And Ernie, if you think it 5 appropriate, you might want to go over those with 6 SACHRP because the next go to 405. So, the ones that 7 I just presented. 8 CHAIR PRENTICE: Yes. Let's go over each 9 of those recommendations and see if we can reach a 10 consensus on the acceptability. 11 MEMBER FISHER: Yes, yes. Okay. So, I 12 think I'll just end. Okay. 13 MEMBER JONES: So, Celia, when you were 14 going through, you explained what you meant by 15 credible argument to us, but that, you know, it can't 16 just be it's an argument that makes sense but it has 17 to be supported by literature and things like that. 18 Is that -- would that be clear to everyone or would 19 there by some misinterpretation about what the level 20 of support you had to have for your -- 21 MEMBER FISHER: Wait, wait. Are we on 22 recommendation one? 23 1 CHAIR PRENTICE: No. 2 MEMBER JONES: Are you just doing one? 3 CHAIR PRENTICE: Yes. 4 MEMBER FISHER: Yes. 5 CHAIR PRENTICE: We're going to go -- 6 MEMBER FISHER: Yes. 7 MEMBER JONES: Oh, I'm sorry. 8 CHAIR PRENTICE: We're going to go through 9 them sequentially -- 10 MEMBER FISHER: Right. 11 CHAIR PRENTICE: -- so when we get to that 12 particular recommendation, then you should ask that 13 question. 14 MEMBER FISHER: Right. Okay. 15 CHAIR PRENTICE: All right. We've got 16 recommendation one on the screen. 17 MEMBER FISHER: Yes. 18 CHAIR PRENTICE: It's been modified in 19 consideration of comments by SACHRP at the last 20 meeting. Are there any questions, concerns, further 21 discussions with that particular recommendation? 22 MEMBER POWELL: I have a particular 24 1 question. I wonder if there's any requirement, and I 2 don't know, but there's a requirement that when the 3 investigator seeks to get the norm to the community 4 that it truly reflects the cultural and ethnic 5 diversity of that community. How is that done? 6 CHAIR PRENTICE: I think it would depend 7 upon the nature of the study, the purpose of the 8 study, the target population of the study. And, as I 9 recall our discussion last time, we did consider that 10 and that was perhaps the genesis of when appropriate. 11 Because, in some cases, you would want to go beyond 12 simply having one community representative on the IRB 13 that would provide that input. You may want to do 14 actually community consultation. So, it's really 15 dependent upon, you know, what the study is all about 16 as to how extensive you would try to ascertain the 17 norms of the community from which the subjects would 18 be drawn from. 19 MEMBER POWELL: The IRB determines the 20 acceptability of that information? 21 CHAIR PRENTICE: Yes. Correct. 22 Yes? 25 1 MEMBER JONES: In this recommendation, 2 will this be in guidance? Just refresh -- or would 3 this be regulation itself? 4 MEMBER FISHER: No. 5 CHAIR PRENTICE: Guidance. 6 MEMBER JONES: It would be guidance. 7 Okay. 8 CHAIR PRENTICE: Yes? 9 MEMBER KORNETSKY: It's all guidance. I 10 think the problem is working in this very practically 11 every day, IRBs often don't know what to think about 12 in applying this waiver as it pertains to pediatrics. 13 So, these are some guidelines of things that they 14 should be thinking about and it really is -- it is 15 guidance. It definitely is not regulation and not 16 meant to be prescriptive of that way. 17 CHAIR PRENTICE: Felix? 18 MEMBER GYI: More and more there has been 19 a movement towards IRBs actually monitoring the 20 activities of the investigators. Yesterday we had a 21 discussion lead by Dr. Schwetz about where the 22 greatest harm is, and that's on the investigator 26 1 level, and how the IRB might play a role. 2 And so, and perhaps this might not be the 3 question for this particular set of recommendations, 4 but I wonder how, even in the form of guidance, the 5 IRBs will be looked at and monitoring the assurances 6 that we're putting in place here to make sure that the 7 investigators are behaving appropriately and 8 especially in the pediatric realm. You know, we are 9 asked for a lot of assurances from the investigator to 10 meet certain ethical and regulatory guidelines and I 11 wonder if this should be in the form of the guidance 12 as well to remove -- 13 MEMBER FISHER: It's already there. 14 MEMBER GYI: -- the burden from the 15 investigator and have some level of mutual assurance 16 and mutual accountability. 17 CHAIR PRENTICE: I would say that that is 18 an issue that extends beyond simply pediatric 19 research. When an investigator submits a protocol to 20 the IRB and the investigator responds to all the 21 questions that are in a typical IRB application, that 22 deal with how the investigator intends on protecting 27 1 human subjects, how the investigator intends on 2 complying with applicable federal regulations, how the 3 investigator intends on complying with institutional 4 policies, you know, I consider that, once it's 5 approved by the IRB, to be a contract between the 6 investigator and the institution and, by extension, 7 the IRB, who is acting as an agent of the institution. 8 You know, that's the trust aspect. You 9 trust the investigator to carry out their 10 responsibilities in an ethical way, the way they said 11 they would do so. You know, but now we're in an era 12 where it's not only just trust the investigators, also 13 verify whether or not the investigator has, you know, 14 has complied. And we do that various mechanisms which 15 are called by various names, such as quality 16 improvement, quality assessment, and some places call 17 it auditing. 18 While I understand where you're going with 19 this, I don't think it's directly, you know, linked to 20 the interpretation of subpart D. It's a separate 21 issue that we can certainly get into as a committee, 22 but I don't think we need to incorporate that kind of 28 1 monitoring in our interpretation of subpart D. I'm 2 certainly willing to have that put on the floor for 3 discussion but I would rather we do that, Felix, at 4 the end of going through the recommendations because 5 it would apply to all our recommendations. Would that 6 be acceptable? Okay. 7 All right. We have recommendation number 8 one on the table. Further discussion? 9 (No response.) 10 CHAIR PRENTICE: I'll entertain a motion 11 then. 12 MEMBER SELWITZ: I move acceptance of this 13 recommendation -- 14 MEMBER GYI: Second. 15 MEMBER SELWITZ: -- provided that this is 16 set forth as guidance. 17 CHAIR PRENTICE: Yes. It's all guidance. 18 All right. We have a motion to approve and a second. 19 You're doing much better than you did yesterday 20 morning. 21 (Laughter.) 22 CHAIR PRENTICE: Any further discussion? 29 1 (No response.) 2 CHAIR PRENTICE: All those in favor? 3 (Unanimous show of hands.) 4 CHAIR PRENTICE: Are any opposed? 5 (No response.) 6 CHAIR PRENTICE: Any abstentions? 7 (No response.) 8 CHAIR PRENTICE: Recommendation number one 9 is approved. Move on to recommendation number two. 10 MEMBER FISHER: Okay. 15 -- okay. It's 11 on the slide. 12 CHAIR PRENTICE: Okay. This was also 13 modified in consideration of SACHRP requirements. 14 And, as I recall, the asterisk was probably the 15 little, the note in the asterisk, was probably 16 something that generated some discussion last time. 17 So, I think it's fairly clear from this 18 recommendation that, you know, we should not be 19 waiving parental permission simply because of cost 20 factors or convenience factors but we're not excluding 21 those from consideration in a sense of trying to be 22 practical about these things as long as it does not 30 1 weaken the protection of the rights and welfare of the 2 human subject. 3 So, that's a little bit of wiggle room 4 that was introduced into that recommendation based 5 upon the discussion last time, as I recall. 6 So, let's -- any discussion, questions? 7 Ada Sue. 8 MEMBER SELWITZ: Susan, Celia, I'm having 9 trouble articulating. I have concerns about this but 10 it's not -- I have not been able to articulate it. 11 And some of it gets back to this issue of guidance 12 versus requirement because it reads the IRB should 13 require investigators to provide. Now, that doesn't 14 sound like guidance to me. That sounds like here are 15 three criteria. You've got to meet these criteria and 16 if you don't meet these criteria, you can't conclude 17 that it's not practicably possible. 18 And I believe there are a variety of 19 different types of studies involving children, many of 20 which sometimes involve existing data, for example, 21 with children. And I'm not convinced that you have to 22 have each one of these criteria met in order to 31 1 determine practicably. 2 So, given the tone of how it's written and 3 the fact that I believe there could be some viable 4 instances, particularly with existing data, that 5 perhaps you don't need to meet all of these 6 practicably. I came away not so much uncomfortable, 7 I mean, I like the modified better than what we saw 8 last fall, but I don't come away feeling reassured 9 that this is guidance. It reads to me like it's 10 federal criteria and we've got to address each one and 11 we have to meet each one before we can make a 12 practicably as opposed to saying here's things the IRB 13 should consider. And I'd just like to get your 14 reaction. 15 MEMBER KORNETSKY: Reading this again, a 16 couple months after this, Ada Sue, I see where you 17 could come up with that. May I suggest, saying to 18 determine whether parent permission can be waived 19 under 46.116(d) because research cannot be practicably 20 carried out, the IRB should take into consideration 21 issues such as? Is that what you're suggesting? 22 MEMBER SELWITZ: I think that, in my mind, 32 1 that would be more appropriate. I think these are 2 excellent criteria. What makes me uncomfortable is 3 the concept that, in all cases, we have to meet. And 4 the minute we start saying we have to meet, then we 5 have to document, we know that that's the next step, 6 each one of these. 7 So, I think that would make me feel more 8 comfortable about this provision. 9 CHAIR PRENTICE: Let me give you some 10 alternate reading. I understand exactly where you're 11 going on this and I agree with it. I just want to 12 throw out alternate reading for consideration, not 13 that I prefer it, but I want to have another way of 14 expressing what you're trying to say. 15 The IRB should require investigators to 16 provide, as appropriate in consideration of the nature 17 of the study, A, B, C. That's a little bit stronger 18 than take into consideration. It's placing more of 19 the responsibility upon the investigator to go ahead 20 and do this. So, I just throw that out for 21 consideration. 22 MEMBER FISHER: Yes, I'd like to say 33 1 there's two points here. And the issue -- I'm 2 confused, too, the issue of whether you put a should 3 in guidance or not. You know, how IRBs interpret 4 guidance, whether they should, whatever, whether they 5 think of a point of consideration or should once it's 6 in guidance, I think these are things that -- I know 7 that, Ada Sue you've been rightly concerned about not 8 having more check-off points. And it is hard to write 9 any type of guidance that IRBs may not interpret that 10 way. 11 I think the -- I like Ernie's proposal 12 because it says as appropriate. I wouldn't, I guess 13 I'd want an example in which it would not -- these 14 requirements would not be important to an IRB. And if 15 they're not important, they're not appropriate, and 16 how would they ever interfere with an IRB judgment? 17 I don't see them as reducing flexibility. One of the 18 things that we've been trying to do over the years 19 that we've been working on this, is to provide IRBs 20 with more support for them to ask the investigator for 21 supporting information rather than for them to 22 constantly have to try to figure out themselves 34 1 whether or not this is really safe. 2 So, the fact that the investigator needs 3 to provide this, does not mean that there is a -- the 4 IRB is still free to make judgments on each of these 5 points, but now they have the information. So, I 6 guess the question really is, I like Ernie's, the as 7 appropriate but, other than that, what harm does this 8 do to IRBs, as long as the whenever appropriate is in 9 there? 10 MEMBER SELWITZ: I didn't mean to imply 11 that it would do harm to IRBs or research. I am 12 concerned, and I've said this so many times that you 13 all are glad this is my last day, how guidance can be 14 taken and used. And I do believe having seen so many 15 different protocols, you periodically find a protocol 16 that you can conclude it's not practicable. You know, 17 or you would conclude that it's not practicable. But 18 could you absolutely say it would always meet these 19 three? I would hate for it to be absolutes and that 20 is why I think Ernie, I'd like to see it written, but 21 I believe what Ernie proposed is excellent. 22 MEMBER FISHER: I just put it up. Did I 35 1 put the phrase in the right place, Ernie? I'm sorry, 2 let me make it white. 3 But anyway, the notion is IRB should 4 require as appropriate within the context of the 5 research, investigators to provide -- or should that 6 go at the end? 7 CHAIR PRENTICE: I would put down the IRB 8 should require investigators to provide within the 9 context of the research -- 10 MEMBER FISHER: To provide as appropriate, 11 okay. 12 CHAIR PRENTICE: -- something like that 13 because that just doesn't flow -- 14 MEMBER FISHER: I know. 15 CHAIR PRENTICE: -- very well. 16 MEMBER SELWITZ: Can I ask a question? 17 Because Susan had proposed alternative language and is 18 it -- I mean I'm trying to get at why it is we have to 19 say investigators have got to address each one of 20 these issues? 21 MEMBER FISHER: Well, let me just ask you, 22 from an ethical perspective, would you want a waiver, 36 1 would you want to waive something if in fact there was 2 another scientifically valid way to do it? Would you 3 want to waive parental permission? 4 In other words, why don't you, let's look 5 at these and decide whether or not any of them are 6 something that we would not want an investigator to 7 consider. I think that's the -- you know, let's look 8 at it the other way. 9 MEMBER SELWITZ: Let me give you an 10 example of what I'm concerned about. And you may say, 11 ethically, that my example is unacceptable. 12 Many students getting masters and Ph.D., 13 going through their degree programs, do thesis and 14 dissertations and, quite frankly, I think it is 15 conceivable that some of those projects, even though 16 it would practicably not be possible, such as using -- 17 wouldn't meet this criterion as absolutely as I read 18 it. So, quite frankly, what has driven my -- I mean 19 I just tried to sit down and think about the range of 20 studies I see, and for some of protocols that involve 21 students-in-training so to speak, masters and 22 dissertations, I think it's possible that there could 37 1 be scientific alternatives. Now, there comes the rub 2 whether ethically you find that acceptable or not. 3 But if it's minimal risk, and it doesn't adversely 4 affect the right and welfare and, in fact, practicably 5 they'd have no way of reaching the parents because 6 they're working with records, for example, then is the 7 answer we're going to say well you can't do that 8 study? And so -- 9 MEMBER FISHER: Let me just say I think 10 there's flexibility for that example. C says a 11 reasonable argument that alternative methods to obtain 12 parent-guardian permission are not feasible. Now, 13 that provides some leeway if in fact they're 14 restricted to a particular population because they are 15 students, it's not grant money, they are a student 16 that's there. A reasonable argument that signed 17 validity would be compromised, that does not preclude 18 various methodologies. It just says that you 19 shouldn't jeopardize in any way a child's right to be 20 protected by their parent, if what you're doing is not 21 valid research. 22 I think that if you're training scientists 38 1 at the masters or doctoral level, you should be 2 training them to do valid research and certainly not 3 sacrificing the rights of children for their training. 4 I just don't think that's responsible mentoring. 5 MEMBER SELWITZ: And it could be that I am 6 reading it too literally because I'm not proposing 7 that they do invalid research. 8 MEMBER FISHER: Right. 9 MEMBER SELWITZ: It's the level to which 10 this is applied. And so perhaps I am just, I will say 11 I will accept Ernie's language. 12 CHAIR PRENTICE: Felix? 13 MEMBER GYI: It is like I agree with your 14 comments and I think, perhaps, for a different reason. 15 The way it's written up there as opposed 16 to how you have suggested, Susan, I find your 17 suggestion much more palatable because it sort of 18 shares the responsibility. The way it's written, it 19 makes the IRB, to use your terms, Celia, a mentor in 20 adequate design and appropriate design and I don't 21 think that's where it ought to be. I think that the 22 IRB ought to have some guidelines in terms of what's 39 1 approvable. But in terms of making the IRB 2 responsible for making the investigator submit 3 something that is scientifically valid is where I have 4 a hard time with this process or with the language. 5 In principle, I agree with all of those 6 things. In practice, I think what's going to happen 7 is that the IRB is then held accountable to having a 8 checkbox mentality to say is this done, is this done, 9 is this done, and is this scientifically acceptable in 10 the context of research ethics. And I just, I think 11 that that's where the responsibility ought to be 12 placed back on the investigator and to make a plug 13 again for a different topic. You know, I think this 14 is where investigator responsibilities ought to be 15 defined. This is not the IRB's responsibilities. 16 The IRB ought to be looking at what the investigator 17 gives them and says whether it's appropriate or not, 18 ethical or not. 19 CHAIR PRENTICE: So, you're agreeing with 20 the language up there? Is that right? 21 MEMBER GYI: I'm agreeing with the 22 language that Susan had recommended, as opposed to 40 1 making the IRB make the investigator submit something. 2 CHAIR PRENTICE: I don't understand 3 because what Susan suggested was the IRB would take 4 into consideration. Now, that implies that the IRB 5 has the information available to take into 6 consideration. Now, there are two ways to get that 7 information. One is you've got to simply glean it 8 from the protocol and figure it out or two, you ask 9 the investigator to tell you why that they think a 10 waiver is justified utilizing this criteria. 11 I don't like this checkbox mentality and 12 there have been too many IRBs that when they grant a 13 waiver under 116(d), they have a checkbox. You know, 14 won't adversely affect the rights and welfare of the 15 research subjects, check, yes, multiple. But why? 16 And when you start asking investigators to justify 17 why, you'd be surprised how many of them say, I can't 18 justify it and they don't get a waiver because it 19 wasn't justified in the first place. 20 So, I don't see anything wrong with asking 21 investigators to think about the ethics of waiving 22 parental permission. Think about it. And provide 41 1 feedback to the IRB as to why you think that, for 2 example, an alternative method to obtain parent- 3 guardian permission is not feasible. There is nothing 4 wrong with asking investigators those kinds of 5 questions. 6 MEMBER KORNETSKY: Ernie, you know, I feel 7 like, you know, Dan showed that thing that we're 8 dancing on the head of -- I mean, I think it's really 9 what we've said. A good IRB, if you tell a good IRB 10 that they should take into consideration, you're 11 right. The way that they're going to take into 12 consideration is to ask the investigator to get it. 13 Or, if an IRB wants to spend the time looking at a 14 protocol and saying it's in here, I think that that's 15 acceptable. 16 I mean, I see the concerns here with the 17 language and a require. I mean, I'm concerned about 18 that as well. I feel much more comfortable saying 19 these are things, these are principles, these are 20 things that you need to take into consideration and 21 leave it to the IRB how it wants to take that into 22 consideration and get that information. 42 1 CHAIR PRENTICE: That's a good point. 2 Yes? 3 MEMBER POWE: I'd like to echo that. I 4 actually think the new language doesn't, in my mind, 5 help because I think these things are always 6 appropriate to take into consideration. 7 So, I like the proposal of taking into 8 consideration and requiring, for that reason. I'm not 9 sure that -- the new language to me is the same as the 10 old language should be. 11 CHAIR PRENTICE: Okay. 12 MEMBER FISHER: So, what would be the 13 language? 14 CHAIR PRENTICE: It would be the IRB 15 should take into consideration, period. 16 MEMBER FISHER: Okay. That -- 17 CHAIR PRENTICE: I understand the 18 rationale. 19 MEMBER FISHER: You see, what I'm confused 20 about -- 21 CHAIR PRENTICE: I think, in a way, that's 22 implied. 43 1 MEMBER FISHER: In terms of Felix's 2 argument, it seems to me this places a greater burden. 3 If the IRB has to take into consideration the 4 reasonable argument that scientific validity would be 5 compromised, without us putting in that the 6 investigator is responsible for providing that 7 information -- 8 MEMBER KORNETSKY: The investigator's 9 always responsible for providing information -- 10 MEMBER FISHER: Okay. 11 MEMBER KORNETSKY: -- in everything that 12 the IRB considers. I mean, we -- then that should be 13 a phrase that's in everything that we do. I mean I 14 think we need to give IRBs some flexibility. 15 I think the important part here is they 16 have things that they can think about when they're 17 applying the waiver. And how they take that into 18 consideration, how they get it from the investigator, 19 whether they want to spend their time going through a 20 protocol that's not obvious in front of them, I think 21 is really up to them. I don't think we should be 22 really prescriptive that way. 44 1 MEMBER POWE: There may even be other 2 things that the IRB might want to take into 3 consideration, other than these three things. And so, 4 it does not limit what they can take into 5 consideration. 6 CHAIR PRENTICE: That's also a very good 7 point. Yes? 8 MEMBER JONES: I guess, the same question 9 I had before about a credible argument, a reasonable 10 argument. And so, I would also like us to turn this 11 around. 12 So, this guidance is really aimed at the 13 IRB community. And so, the other player is the 14 investigator who is now going to be asked to develop 15 these arguments -- 16 MEMBER FELIX: Not necessarily. 17 MEMBER JONES: -- in such a manner so that 18 they can fulfill the things that the IRBs are asking 19 for. 20 And I think we also need to develop 21 guidance for the investigators or some ways that they 22 know, you know, what are ways to develop a reasonable 45 1 argument. I would have a question as a scientist, how 2 reasonable does my argument have to be? Do I have to 3 have data? You know, so I begin to ask different 4 kinds of questions when I would come to trying to 5 fulfill these different requirements. 6 CHAIR PRENTICE: I understand your point. 7 I guess what I'm concerned about is how far we, as a 8 committee, go in terms of providing guidance. I mean, 9 you can take criteria A and you can probably write, 10 you know, a paper on that. It's how far do we go? 11 I guess I would prefer to, you know, to 12 leave it as it is and leave IRBs flexibility so that 13 when an investigator calls the IRB and says look, I'm 14 not quite sure what a reasonable argument that 15 scientific validity would be compromised, could you 16 kind of give me some examples. And let the IRB take 17 care of that as opposed to us trying to be a little 18 bit more prescriptive and more expansive in our 19 guidance because it's going to be a never-ending 20 process. 21 MEMBER JONES: You know, I'm not trying to 22 hold up this particular guidance because I think we 46 1 should go forward with it. I do think, though, this 2 creates, it augments this tension that we keep on 3 saying that, you know, that whose responsibility is it 4 to comply. And if all of the things, not all, but the 5 bulk of the things that are developed are aimed at the 6 IRB community. I think it reinforces the concept that 7 some of my colleagues keep on saying that we've lost 8 the impression that it's all about the investigators 9 who are the primary source for fulfilling these 10 arguments or filling the obligations of protecting 11 human subjects. 12 So, I guess I would also like to consider, 13 you know, is there a way, you know, or ask the 14 committee to consider, you know, what parts of this 15 would investigators need help in order to fulfill 16 their obligations, to not just focus all the attention 17 on the IRB community but to also consider, you know, 18 how can we make this doable for the investigators to 19 be able grapple with, you know, and fulfill the things 20 that we're now, you know, putting back down on them. 21 Maybe it should have been, and I'd say probably the 22 best investigators do that already, but to make sure 47 1 that, you know, that we don't create another barrier 2 or increase the tension between the IRB and regulatory 3 community and the investigators. 4 CHAIR PRENTICE: Well, you know, this 5 whole concept of an HRPP, shared responsibility which 6 encompasses, you know, not only the investigator but 7 also the IRB. It involves education, it involves 8 training, it involves guidance, it involves all of 9 that. So, I would think it would be an obligation of 10 any IRB to work with investigators to try to interpret 11 the guidance which is issued by OHRP that reflects the 12 requirements of subpart D or subpart A or any other 13 aspect of the common rule. 14 You know, we're not going to be able to 15 write a tome that is prescriptive, and this is how you 16 look at this and this is how you look at that. You've 17 got to leave some flexibility to IRBs and to 18 investigators to kind of sort this out. We've been 19 dealing with 116(d) since 1981. It hasn't changed. 20 Okay? This is more guidance than we've ever had and 21 I don't see us trying to go too much further, but I do 22 see us presuming, okay, that IRBs will work 48 1 investigators. 2 All right. Are you happy with the 3 language? Take into consideration. 4 MEMBER SELWITZ: Happier. 5 CHAIR PRENTICE: Happier? 6 (Laughter.) 7 CHAIR PRENTICE: Okay. Further 8 discussion? 9 (No response.) 10 CHAIR PRENTICE: Are we ready to vote? Is 11 there a motion? 12 (Laughter.) 13 MEMBER GYI: I'll go out on a limb. 14 CHAIR PRENTICE: Did you -- 15 CHAIR FISHER: I don't understand the -- 16 I don't think -- it's not clear to me what the concern 17 is, at this point. I understand your concern, but we 18 decided to take investigator out of this kind of 19 recommendation to give IRBs more flexibility in how 20 they want to acquire that information. 21 So, it seems to me that this is not overly 22 burdensome on IRBs that the issue which I think is 49 1 important that investigators need guidance, I don't 2 think we can work for, under subpart four, or 3 whatever, subpart D. So, then the question is, I 4 don't think anybody has a problem with a, b, c as 5 legitimate points for an IRB to consider. So, you 6 know, I'm just trying to articulate that once we've 7 changed the should to consider, I don't see that the 8 group has had problems because nobody's raised any 9 issues about a, b, or c. 10 MEMBER GYI: I would agree. And, before 11 I make the motion, I just wonder, Mr. Chair, if 12 there's any latitude for us to hear from the ex 13 officios that are sitting around the table, if they 14 have any other comments. I mean, you know, these are 15 issues that are going to impact some of these members 16 there. 17 CHAIR PRENTICE: There is all the latitude 18 you want. Do any of the ex officios wish to comment 19 on recommendation number two? 20 MEMBER BARRATT: Just to say that I 21 thought the original wording that was offered in 22 response to your comment, or as part of your comment, 50 1 was included as such as. 2 UNIDENTIFIED SPEAKER: No, that is right. 3 MEMBER BARRATT: And that would be a much 4 more kind of gentle wording that's informative without 5 being prescriptive. 6 MEMBER SELWITZ: I actually would agree 7 with that because you're right, Susan said such as, to 8 take into consideration such as. And that would, in 9 fact, I think it would be appropriate to add such as. 10 Should take into consideration -- how did you say it, 11 Susan? Because you did -- 12 MEMBER KORNETSKY: Issues such as. 13 MEMBER SELWITZ: Oh. Yes, I would fully 14 support that because, just as Neil said, there's often 15 going to be additional issues. 16 CHAIR PRENTICE: Okay. 17 MEMBER POWE: I'd just like to weigh one 18 more point. The wording as it is would not preclude 19 an IRB from having check boxes, should it wish to have 20 check boxes for these items or to educate its 21 investigators about these issues. So, you know, so it 22 provides that flexibility at each institution. 51 1 MEMBER GYI: Now that we've gotten that 2 discussed, I'd like to make a motion to approve the 3 recommendation as it appears on the screen. 4 MEMBER SELWITZ: Second. 5 CHAIR PRENTICE: Okay. Further 6 discussion? 7 (No response.) 8 CHAIR PRENTICE: All those in favor? 9 (Unanimous show of hands.) 10 CHAIR PRENTICE: Any opposed? 11 (No response.) 12 CHAIR PRENTICE: Any abstentions? 13 (No response.) 14 CHAIR PRENTICE: Recommendation number 15 two, as modified, approved. Let's move on to three. 16 Okay. I don't remember whether or not 17 this was modified. It doesn't indicate that it that 18 it was. 19 MEMBER FISHER: No. I don't think it was. 20 CHAIR PRENTICE: And I can't remember what 21 the problem was, if any, last time. It's -- the 22 rationale for this particular recommendation is the 52 1 fact that the regulations 408(c) give an example, 2 which may lead IRBs to think that that is the only 3 example. So this was to increase the flexibility of 4 interpretation of 408(c) to allow other situations. 5 So, any discussion, concern? Yes? 6 MEMBER JONES: Well one thing that came to 7 mind on this was just, I guess this is sort of like a 8 comment and then you can answer or respond, is that 9 what level of evidence, and this would be left up to 10 the IRB judgment I guess, I would assume, like if this 11 was a rare occurrence or, you know, like if this was 12 a real danger. You know, like in this particular 13 example or say only, you know, a small percentage of 14 the parents would actually provide this conflict. So, 15 it would be left up to the judgment of the IRB to say 16 whether or not they would feel comfortable waiving 17 based on, you know, the evidence that the investigator 18 provided, like if there is a ten percent chance there 19 would be risk, you know, to the children or something. 20 And I guess that's my question is, there 21 still would be flexibility for the IRB to go with 22 their best judgment. 53 1 MEMBER KORNETSKY: There would have to be. 2 I mean, it's looking at the risks. And, you know, we 3 never put numbers around, there has to be a 50 4 percent, you know, risk that, you know, this would 5 impact the child or whatever. And it will vary 6 according to whatever the condition is as well. 7 MEMBER JONES: Right. 8 MEMBER KORNETSKY: So, I don't think this 9 is limiting the flexibility at all. 10 CHAIR PRENTICE: Okay. This -- I'm a 11 little confused about the numbering here. 12 MEMBER FISHER: Yes. I'm sorry. 13 CHAIR PRENTICE: I assume that that is -- 14 it was modified. So, we've got, that is really 15 recommendation number, that's number three. The next 16 one is number three as well, is it not? 17 MEMBER FISHER: No, it's number four. But 18 I think that what Nancy was pointing out is that in 19 looking at three, we really need to look at four in 20 terms of what do we mean. What kind of guidance are 21 we going to give in terms of how do you include things 22 outside of abuse and neglect. So, I think she was -- 54 1 CHAIR PRENTICE: Okay. 2 MEMBER FISHER: -- seeing them as linked, 3 even though they're two different recommendations. 4 CHAIR PRENTICE: Okay. 5 MEMBER FISHER: So, did you want to -- 6 CHAIR PRENTICE: Well, I think you almost 7 have to go to number four before -- 8 MEMBER FISHER: Right. 9 CHAIR PRENTICE: -- before you can act on 10 number three. 11 MEMBER FISHER: Right. So, remember 12 number four is two pages. This one and then the 13 adolescent. Two slides, I mean. 14 CHAIR PRENTICE: Let's everybody review 15 number four once again. And I think the key point on 16 this particular slide is, "has to satisfy all of the 17 following." 18 MEMBER FISHER: No. No, it's or. Or. 19 They're all or. 20 CHAIR PRENTICE: No. 3(a)? 21 MEMBER FISHER: Oh, I'm sorry. Now you're 22 in this. 55 1 CHAIR PRENTICE: I'm on -- 2 MEMBER FISHER: Yes. 3 CHAIR PRENTICE: Okay. It satisfies all 4 of the following. So, I want you to focus on that 5 and see whether or not you're comfortable. 6 MEMBER SELWITZ: Let me ask you all a 7 question. So, if you had a research study in which 8 there was no direct benefit to those subjects. All 9 right? That's a minimal risk study. Okay? And it 10 might -- 11 MEMBER FISHER: If it's minimal risk, it 12 goes under 116. 13 MEMBER SELWITZ: All right. Well, let's 14 say it's greater than minimal risk. Sorry, Celia. 15 But there's no direct benefit. All right? Would it 16 automatically mean -- well, if it's greater than 17 minimal risk we're talking about, but we're waiving 18 parental permission -- let me talk through this. 19 Forgive me, I'm not as sharp as you all are in terms 20 of following this. So, greater than minimal risk, not 21 -- we're waiving parental permission, but we still 22 could get assent from the adolescents. All right? 56 1 But if there was no direct benefit to that adolescent 2 for participation, would these conditions then mean 3 that we could not waive parental permission? 4 MEMBER FISHER: No, no. In fact -- 5 MEMBER SELWITZ: Okay. 6 MEMBER FISHER: -- that's what -- right. 7 This is for research that is very relevant 8 to the types of treatments that adolescents can get 9 without parental permission. The research itself may 10 not be intervention research. It could be just, you 11 know, what are the emotional reactions following a 12 procedure or how adequately do adolescents understand 13 what they are saying that they want. So, it's not the 14 intervention itself. 15 It's saying that if the topic of the 16 research and the types of questions that are being 17 asked are commensurate with the medical or 18 psychological treatment that the child is permitted to 19 receive without parental permission, in some sense 20 it's inconsistent to require parental permission for 21 them to be asked about that research, asked about 22 those questions within the context of that. And, in 57 1 fact, would impede research because the adolescents 2 will not want to be -- those adolescents who are 3 engaging, you know, who are getting their entitled 4 services without parental permission, may not be 5 comfortable in asking a question. Then they become 6 research orphans for that particular issue. 7 MEMBER KORNETSKY: Celia, I just want to 8 ask you a question, also. We're chairs and I'm asking 9 her a question -- 10 MEMBER FISHER: No, no. 11 MEMBER KORNETSKY: -- but that's all 12 right. 13 MEMBER FISHER: I ask you questions all 14 the time. 15 MEMBER KORNETSKY: All right. You have, 16 and this is not something that was clear to me, when 17 we're presenting this as, you had made the comment 18 well if it's minimal risk you go to subpart A, if it's 19 greater than minimal risk, you go to subpart D. 20 MEMBER FISHER: Subpart D, too, though. 21 MEMBER KORNETSKY: You could -- I just 22 want to make it clear -- 58 1 MEMBER FISHER: Okay. Right. You're 2 right. 3 MEMBER KORNETSKY: -- that it's not -- 4 it's either or. I mean, and I don't want to -- 5 MEMBER FISHER: No, you're absolutely 6 right. I realize that. 7 MEMBER KORNETSKY: It's not automatically 8 go to subpart A. 9 MEMBER FISHER: Right. You could -- 10 MEMBER KORNETSKY: So, this could fit for 11 certain minimal risk research. 12 MEMBER FISHER: Right. 13 MEMBER KORNETSKY: But there's an option 14 that IRBs could use either mechanism -- 15 CHAIR PRENTICE: Yes. 16 MEMBER KORNETSKY: -- for waiver. 17 MEMBER FISHER: Yes. 18 MEMBER KORNETSKY: I just want to -- 19 MEMBER FISHER: You're absolutely right. 20 MEMBER KORNETSKY: -- make that clear. 21 CHAIR PRENTICE: Okay. Yes, Neil? 22 MEMBER POWE: Just in looking -- 59 1 MEMBER FISHER: No, no. I realized as 2 soon as I said it, it was wrong to say. 3 MEMBER POWE: I'm a little concerned about 4 3(d) here, whether 3(d) always applies. And the 5 reason I'm saying that is that it's linked to 6 treatment. And is all the research that would fall 7 under this linked to treatment? 8 MEMBER FISHER: Yes. You know, that's a 9 good point. We might want to change it to services. 10 Is that what you're saying? 11 MEMBER POWE: Yes. That's what I'm 12 getting at. And so, when it says satisfies all, it 13 may be that D doesn't even apply. 14 MEMBER FISHER: Right. Yes. 15 MEMBER POWE: It may be that D doesn't 16 even apply as now written. 17 CHAIR PRENTICE: I think that I take your 18 point. If you substitute services then if you note 19 commensurate, that would suggest that there just 20 simply has to be commensurability. It doesn't say 21 there has to be a duplication. 22 MEMBER FISHER: Right. 60 1 CHAIR PRENTICE: It has to be similar. 2 Would that satisfy your concerns? 3 MEMBER POWE: That's better. That's 4 better. 5 CHAIR PRENTICE: Okay. So, you've already 6 substituted services in there. All right? 7 MEMBER FISHER: Because it remains a very 8 conservative, in some sense, waiver because it's -- 9 and it's very community sensitive, in some sense, 10 because it's saying if the state law -- it's going by 11 state law. So, if the state law has decided that 12 these adolescents, for whatever reason, do, you know, 13 have the right to consent without parental permission 14 that research that is commensurate with what the state 15 has already decided should also be able to be 16 conducted. So, it is a protective measure. Yes. 17 CHAIR PRENTICE: Pardon me? 18 UNIDENTIFIED SPEAKER: Behind you. 19 MEMBER FLANZER: So, if the state law is 20 silent on -- I don't even want to use the phrase 21 emancipated minors, but if the state law is silent on 22 this issue on receipt of services or treatment, what 61 1 happens to the IRB trying to fulfill D? 2 MEMBER FISHER: They can't. But then they 3 might -- then the question is, why are they waiving 4 it? And then they might go to one or two. 5 MEMBER KORNETSKY: Most state laws are 6 silent on areas of research. 7 MEMBER FISHER: No, she meant on services. 8 MEMBER KORNETSKY: On services. 9 MEMBER FLANZER: On the services or 10 treatment for the commensurate research. 11 MEMBER FISHER: Remember, what I'm trying 12 -- I think that's an excellent question. 13 If it's minimal risk research, then they 14 can go to 116(d), if they want. If it is a minor 15 increase over a minimal risk, the question is, how 16 much flexibility do we want an IRB to have in terms of 17 waiving parental permission? Under what guideline 18 would they do that? Well, they can do it if, in fact, 19 they demonstrate that informing the parent would be 20 harmful to the child or that there's some conflict in 21 the parent's role that they could not use that. 22 And, you know, I think you're raising a 62 1 great point in the sense there will be research that 2 cannot be approved because it may not fit in. But the 3 question is, is there other types of guidance that we 4 could put in that would make special circumstances for 5 adolescents in greater than minimal risk research to 6 waive parental permission? You know, there may be 7 some suggestions here, I just don't know what it is. 8 MEMBER FLANZER: The thing I'm trying to 9 avoid, Celia, is that the -- 10 MEMBER FISHER: The sound was coming from 11 there. 12 MEMBER FLANZER: -- is that the IRB does 13 not exercise their flexibility, their thoughtfulness, 14 their careful processing as they -- and move to a 15 check box approach where it seems as though these are 16 the conditions they must apply. And I don't want, 17 necessarily, to add a point E that says or exercises 18 thoughtful discussion about, but I would -- I can't 19 think of language to do that. 20 MEMBER FISHER: What if -- right. What 21 if, and when appropriate involves experiences? 22 MEMBER FLANZER: I think we were trying to 63 1 be -- 2 MEMBER FISHER: Are you thinking D is too 3 restrictive? 4 MEMBER KORNETSKY: Well, I think we were 5 trying to be restrictive in this. 6 CHAIR PRENTICE: Well, you know -- 7 MEMBER KORNETSKY: I think we were trying, 8 you know, really sort of limit. Again, there are 9 other options for waiving parental permission in 10 greater than minimal risk research. And I think this 11 is really just for adolescent and we were trying to be 12 careful and, I think, responsive to some of SACHRP's 13 concerns last time, that it isn't totally open ended. 14 That we do take this very seriously and not make it 15 too easy, just because they're an adolescent to waive 16 parental permission. 17 So, you know, maybe it is too restrictive 18 but I think, in this case, we did really, we did want 19 to put some limits around it. 20 MEMBER SELWITZ: A question, Ernie. 21 CHAIR PRENTICE: I'm sorry, what? 22 MEMBER SELWITZ: Can I ask a question? 64 1 CHAIR PRENTICE: Yes, sure. 2 MEMBER SELWITZ: I'm trying, and again, 3 Sally, like you, when I, the minute I saw and 4 satisfies all of the following, I'm trying to, you 5 know, when I was on the plane reading this, I was 6 trying to think through what were the implications. 7 And I'm back to the old issue of clinical research 8 versus social science research. Because we apply this 9 to huge range. 10 So, if you talk about treatments, Neil, I 11 couldn't agree with you more, that implies. Even if 12 you say services, what if the service is not related 13 to health? I mean, I don't even know if I like the 14 word services versus treatment and yet we'll be left 15 with something where we've got to apply them all. And 16 if you've ever looked at my state law, you'd know that 17 that would not necessarily be so easy to figure out in 18 some cases. 19 But, I'll just put it to you all. If you 20 take off your clinical hat and you're thinking about 21 strictly social science research, you know, does -- 22 what does this do? And I'm not saying I'm against it. 65 1 I just haven't been able, I haven't spent the hours 2 you all have spent on it. But like even the first 3 statement, important to the health and well-being of 4 the subject population. And some of the research that 5 we see and, again, admittedly, HHS is focused on 6 predominant health issues, but we take these rules and 7 apply them to a broad group of research projects that 8 often have nothing to do with well-being of subject 9 populations, per se. I mean it might. 10 I just throw this out because I haven't 11 spent the hours that you all have spent on it. And 12 whether you think that this is overlooking the social 13 science perspective, or even the educational research 14 perspective. 15 MEMBER FISHER: How about health, 16 development or well-being of the subject population? 17 I guess the question is, if it's above a 18 minor increase over minimal risk, does it have to be 19 more important in some way? We were trying, you know, 20 in some sense you can see the influence here of 406 in 21 our thinking. 22 There's two issues here. One is we don't 66 1 want give free reign to waiving parental permission 2 for adolescents. And, as we've discussed previously, 3 every researcher thinks that their research is really 4 important. So, the question -- and if it's only 5 minimal risk, they can waive it under 116. 6 The issue here is two-fold. One is, how 7 do we provide flexibility so that we're doing the 8 research on adolescents that could not be done if 9 parental permission is required. But that it's 10 important enough that we would want it to be done. 11 And the D part is really very directly related to 12 social scientists who have been arguing that the -- as 13 well as nonsocial scientists, that the emancipated 14 minor laws have not been adequately utilized by IRBs 15 in terms of permitting certain very relevant research 16 for adolescents. 17 So, D really did evolve from the 18 emancipated minor laws. 19 MEMBER KORNETSKY: I think it's the mature 20 minor. Many times -- 21 MEMBER FISHER: No, I'm sorry. You're 22 right. Thank you. Mature. 67 1 MEMBER KORNETSKY: Mature minor. 2 MEMBER FISHER: Thank you. I'm sorry. 3 MEMBER KORNETSKY: Emancipated you don't 4 have to think about these -- 5 MEMBER FISHER: Absolutely. You're 6 absolutely right. 7 MEMBER KORNETSKY: So, it's the mature 8 minor laws which have to do with it. Okay. 9 MEMBER FISHER: Thank you. Right. 10 MEMBER FLANZER: Well, Celia, what about 11 then flipping D around, so that it begins with, when 12 state laws exist governing mature -- activities 13 related to mature minors, the IRB is encouraged to 14 apply those in ways that? 15 MEMBER FISHER: Something like that? 16 MEMBER KORNETSKY: When mature minor state 17 laws are relevant? Is that what you're trying to get 18 at Sally? 19 MEMBER FISHER: Because I think -- it may 20 not be worded well, but I think something like this 21 addresses Sally's concern that we are, there may be 22 research that's important to do and meets all the 68 1 other criteria but there's no state law even on the 2 services. 3 MEMBER FLANZER: Right. 4 MEMBER FISHER: Right. I don't know if 5 that's worded right, but it's trying to -- 6 MEMBER FLANZER: That'S the idea. 7 MEMBER FISHER: Yes. Pertinent? I don't 8 know. 9 See, I think this is interesting from 10 FDA's perspective as well, if they ever consider 11 waiving parental permission, the mature minor laws, it 12 would seem to me, might be the only place that you 13 would consider doing that. And whether this is 14 helpful to you or not, I'm not sure. 15 MEMBER LEPAY: Yes, I'm watching the 16 wording very carefully. 17 MEMBER FISHER: Yes. 18 MEMBER LEPAY: I'm not sure we have the 19 right wording here yet either, -- 20 MEMBER FISHER: Right, right. 21 MEMBER LEPAY: -- but you're working on 22 it. 69 1 I'm also, of course, watching the issue 2 that we're not talking about investigational products. 3 And the way this is phrased, of course, you are 4 precluding investigational products because the state 5 law could not permit the use of an investigational 6 product. 7 MEMBER FISHER: Right. True. 8 MEMBER LEPAY: So it may, you know, it may 9 work out fine from our perspective. I'm just not sure 10 how better to tweak the wording. 11 MEMBER FISHER: When state laws apply? 12 CHAIR PRENTICE: You know, the -- I'm 13 looking at subpart D and trying to find the regulatory 14 language that was the genesis of that. And, unless 15 I'm missing something, the only thing I can find, I 16 can find two sections that seem to indirectly address 17 that. One is that it refers to the research protocols 18 designed for conditions or for a subject population 19 for which parental or guardian permissions is not a 20 reasonable requirement. And the second is the waiver 21 is not inconsistent with federal, state, or local law. 22 So, it seems to me that what we're talking 70 1 about here is really two things that you're trying to 2 blend into one criteria, that is D. You're saying, 3 number one, there are situations where state law may 4 exist that would prohibit a waiver of parental 5 permission. And you're also saying that state laws 6 may exist that would allow an emancipated minor to 7 consent for various services, okay, which would be 8 commensurate with the research protocol. 9 So, those are two -- 10 MEMBER FISHER: That's very interesting. 11 CHAIR PRENTICE: -- separate things. And 12 I think you need to get that in there and maybe what 13 you need to have is, instead of having one blended 14 criteria which is confusing me and perhaps other 15 people, you need to have two criteria. 16 MEMBER FISHER: You mean a separate one 17 for adolescents? 18 CHAIR PRENTICE: Well, no. A separate one 19 just saying that the waiver's not inconsistent with 20 state law and then have something about the research 21 protocol would be -- would have activities or 22 procedures that are commensurate with services that an 71 1 emancipated minor could legally consent to in the 2 state. 3 Something like that. I mean, I don't have 4 the exact wording down, but it seem to me that that's 5 what you're trying to address here. 6 MEMBER FISHER: Are you saying a D and E? 7 CHAIR PRENTICE: Yes, I'm saying a D and 8 an E. 9 MEMBER FISHER: Yes. So, what -- I put D 10 up there. What would E be? Or? 11 CHAIR PRENTICE: I think what you're 12 trying to say is that in some states, and you guys 13 know more about this than I do, I assume that in some 14 states there are laws on the books that allow an 15 emancipated minor -- 16 MEMBER FISHER: Mature minor. 17 MEMBER KORNETSKY: Mature minor. 18 CHAIR PRENTICE: -- mature minor, okay, to 19 consent for various services -- 20 MEMBER FISHER: Yes, yes. 21 CHAIR PRENTICE: -- like, you know, like 22 birth control or what have you. 72 1 MEMBER FISHER: Right. 2 CHAIR PRENTICE: Right? And perhaps there 3 are other states where that is done but there is no 4 state law. 5 MEMBER FISHER: Right. 6 CHAIR PRENTICE: Would that be fair? 7 MEMBER FISHER: No. I think there's two 8 things. One is trying to, you know, we all know IRBs 9 are, for many reasons, risk adverse. When state law, 10 when the mature minor law is silent when it comes to 11 research, IRBs are reluctant, even though they have 12 the right to do it under regulatory -- current 13 regulations, they are reluctant to waive parental 14 permission. And this is trying to not be mandatory 15 that they must, I think -- and maybe, they always have 16 the right not to waive parental permission, but this 17 is saying if you're thinking about doing that, these - 18 - waiving parental permission, this is what you need 19 to think about. 20 And so, I'm not sure waiver is not -- I 21 like that waiver is not inconsistent with state law, 22 but I don't think it solves the silence of state laws. 73 1 In many states there is no law that says parents have 2 the right to give consent. There are laws, you know, 3 for things like research, you know, must, but there 4 are laws say about treatments and when parental 5 permission is required and when it is not. And E is 6 necessary to help IRBs know that they can look at 7 state laws on mature minors as guides to whether or 8 not these are state norms that say these are the kinds 9 of questions, topics, procedures that we feel 10 adolescents are mature enough to consent to on their 11 own without parental permission. 12 So, I think something like E is necessary 13 to solve the problem that was raised is why we're 14 trying to address this as well as IOM and NHRPAC. 15 It's a big issue for -- especially for, social science 16 research that is not intervention. But it's trying to 17 figure out what are the correlates or consequences of 18 the problems that bring adolescents to these services 19 that state law allows them to get independently. 20 MEMBER SELWITZ: Can I ask another 21 question, just to make sure I'm clear, because it 22 might, you know -- if I understand recommendation 74 1 four, you're proposing three criteria but they are 2 or's between each of the three criteria. 3 MEMBER FISHER: Right. 4 MEMBER SELWITZ: So you can -- and I think 5 that is appropriate. I mean, that helps me work 6 through this, in terms of trying to think about the 7 range of studies. So, it can be item one, or item 8 two, or, if it's item three, then you get into it must 9 be all of these conditions. Have I got that straight? 10 Is that what you're proposing? 11 MEMBER FISHER: Because in this situation, 12 the individual's not able to make a -- 13 MEMBER KORNETSKY: I mean, this again, 14 it's funny. I mean, I would think that this would be 15 the least controversial because this is really closing 16 the door on certain types of things that we feel would 17 be inappropriate. We would not want parental 18 permission waived haphazardly just because someone is 19 an adolescent. So this is grounding it to say to the 20 IRBs, this is okay if it's similar to the types of 21 things that adolescents in your state can go and get 22 done, or evaluated, or treated for without their 75 1 parents' permission, period. That's how this is being 2 limited. It's meant to limit it that way. We don't 3 want kids, you know, going into different types of 4 trials or other types of things without parental 5 permission. 6 So, this is a conservative view, yet one 7 that IRBs feel very uncomfortable. So, this is saying 8 the door's open a little bit, look to your state, see 9 the types of things and then it may be appropriate to 10 think about waiving parental permission in those 11 situations. 12 MEMBER FISHER: I mean, I like it with the 13 D included, you know, and then the E. I think this 14 gives them a lot of guidance in terms of what they 15 should be, what they can consider and, at the same 16 time, is not opening the floodgates for waiving 17 parental permission just because somebody's an 18 adolescent, like Susan said. 19 And I think it satisfies Sally's concern 20 in the sense that, if there are no laws there, then A, 21 B, C become very important, if there's no laws that 22 either impede or give the right for waiver. 76 1 CHAIR PRENTICE: Celia, for number D or 2 letter D, you probably should use the language of the 3 regulations that says the waiver is not inconsistent 4 with federal, state or local laws. 5 MEMBER FISHER: Right. Absolutely. 6 CHAIR PRENTICE: It actually says law, so 7 let's just stick with the -- 8 MEMBER FISHER: Singular? 9 CHAIR PRENTICE: Yes. All right. I'm 10 getting more comfortable with this now. What do you 11 all think? 12 MEMBER FISHER: I have to say I like the 13 suggestions. I think they've made it more flexible 14 but not more harmful to adolescents, in terms of their 15 rights. 16 CHAIR PRENTICE: Yes. 17 MEMBER FISHER: I think this has been 18 going around for 10 to 15 years, this issue, in 19 research, especially basically since adolescents have 20 gotten the right to receive certain services without 21 parental permission, the fact that we can't do 22 research, or IRBs are reluctant -- 77 1 CHAIR PRENTICE: Yes. 2 MEMBER FISHER: -- to permit research on 3 these issues without parental permission, I think is 4 a public health problem for adolescents. So, I think 5 this is an important one that we should approve with 6 language that you're all comfortable with. 7 CHAIR PRENTICE: Felix? 8 MEMBER GYI: Yes, I agree with that. I 9 would make a motion to approve this recommendation as 10 modified. 11 CHAIR PRENTICE: Okay. 12 MEMBER JONES: Second. 13 CHAIR PRENTICE: Okay. It has been moved 14 and seconded. Further discussion? 15 (No response.) 16 CHAIR PRENTICE: All those in favor? 17 (Show of hands.) 18 CHAIR PRENTICE: Any opposed? 19 (No response.) 20 CHAIR PRENTICE: Any abstentions? 21 (One abstention.) 22 CHAIR PRENTICE: Okay. The motion 78 1 carries. 2 MEMBER FISHER: Ernie, did you want to go 3 back to recommendation three? Or is it not -- 4 CHAIR PRENTICE: I think that that's -- I 5 mean, I look at those as -- 6 MEMBER FISHER: Okay. 7 CHAIR PRENTICE: -- four is an extension 8 of three. I think if you've approved four, you've 9 approved three. 10 MEMBER FISHER: Right. Okay. 11 CHAIR PRENTICE: So, both are approved. 12 MEMBER FISHER: Is there anything else? 13 I think that's all for this grouping. 14 CHAIR PRENTICE: Okay. We've got 25 15 minutes before the break. What do you want to do? 16 You want to -- 17 MEMBER FISHER: Sure. 18 CHAIR PRENTICE: -- start moving on? 19 MEMBER FISHER: Okay. Wait a minute. 20 MEMBER JONES: While she is getting set 21 up, I have one question, too. In the guidance, are 22 you all suggesting using the examples? Because, you 79 1 know, frankly, they are very helpful -- 2 MEMBER FISHER: Yes. 3 MEMBER JONES: -- as you're thinking 4 through the issues. 5 MEMBER KORNETSKY: I think that's up to 6 OHRP but all I know is people are constantly asking 7 for examples and, as long as they feel comfortable 8 with them, I would encourage them to use examples or 9 substitute others. 10 MEMBER FISHER: Okay. So, now we're going 11 to be talking about 405, which is research that can be 12 greater than minimal risk but provides the possibility 13 of direct benefit for the child. You may recall we 14 spoke about these issues not last meeting but the 15 meeting before, when we were kind of introducing so 16 many things all together. So, now we've returned to 17 some of these issues. I think we had discussion but 18 we had made no proposals at that meeting where we were 19 just raising these kinds of issues. This would be on 20 page what? This is slide 38, so -- 21 Okay. The types of topics that we 22 addressed is what is acceptable risk, what does 80 1 available alternatives mean, we're going to recommend 2 that there should be evidentiary basis for available 3 alternatives, we addressed monitoring procedures as 4 benefit, Phase I drug studies, Phase I vaccine trials, 5 and component analysis. The much feared component 6 analysis. 7 Okay. So, to remind you, 46.405, the HHS 8 will conduct or fund research in which the IRB finds 9 that more minimal risk to children is presented by an 10 intervention or procedure that holds out the prospect 11 of direct benefit for the individual subject, or by a 12 monitoring procedure that is likely to contribute to 13 the subject's well-being, only if the IRB finds that 14 the risk is justified by the anticipated benefit to 15 the subjects; the relation of the anticipated benefit 16 to the risk is at least as favorable to the subjects 17 as that presented by available alternative approaches; 18 and adequate provisions are made for assent and parent 19 permission. 20 So, we're going to, but what I've 21 underlined in purple or whatever color that is, that's 22 interesting that it looks the same color up there, is 81 1 what we're addressing. So, what is acceptable risk? 2 So, the first proposal is that when 3 research presents the prospect of direct benefit for 4 the subject, the ceiling on risk is determined by 5 whether or not it's proportional to the probability 6 and magnitude of benefit. I don't think this is 7 something new, but we wanted -- it's kind of like a 8 sequencing of underscoring the importance of the risk 9 benefit decision. 10 Available alternatives. As another 11 proposal we recommend, as an additional protection, 12 even if the risks are balanced by the anticipated 13 benefits, a study may not be independently approved by 14 an IRB if the anticipated benefits are not at least as 15 favorable to the subjects as available alternative 16 approaches. 17 Once again, we think we're interpreting 18 the regulations here, we're just trying to provide 19 language that helps IRBs with how they are weighing 20 the risk benefit balance with the available 21 alternatives that are in the wording of the 22 regulation. 82 1 Now, what are available alternatives? We 2 have not directly addressed some of these things, but 3 I do think, maybe later on, to provide, if the SACHRP 4 wants, to provide guidance on whether or not we should 5 be addressing them, is affordable alternatives what is 6 meant by alternatives? For example, if someone can't 7 afford to get available treatments out there, are we 8 considering it then that they can be in a study that 9 has greater than minimal risk with the prospect of 10 direct benefit? Do the alternatives have to be 11 empirically validated? That's not always the case, 12 that the alternatives may just be out there, treatment 13 as usual, clinically accepted but untested treatments, 14 treatment as usual in non-research setting. 15 So, what we tried to do, given all those 16 questions, was say what constitutes evidence of an 17 effective or appropriate alternative, so that IRBs 18 would have some guidance as to what they should 19 consider or could consider as evidence. 20 So the evidentiary basis, so our third 21 recommendation is, evidentiary basis for evaluating 22 available alternatives. Evidentiary evidence can be 83 1 defined in terms of scientific data or comparison to 2 the standard of care for treating or monitoring the 3 subject's disorder. And we took that from the 4 National Commission which said the expectation of 5 success should be scientifically sound to justify 6 undertaking whatever risk is involved. Well, if the 7 expectation of success, if the probability of benefit 8 should be scientifically sound, then standards, the 9 comparison with alternative treatments should, to the 10 extent possible, be scientifically sound. So, it can 11 be defined in terms of scientific data or comparison. 12 Now, the next issue is monitoring 13 procedure. Remember that in the federal regulations, 14 the intervention itself does not necessarily have to 15 have direct benefit if the monitoring procedures will 16 or both may. So, this is a quote from the National 17 Commission: "Greater risk is permissible under this 18 recommendation only if it is presented by an 19 intervention that holds out the prospect of direct 20 benefit to the individual subjects or by a procedure 21 necessary to monitor the effects of such intervention 22 in order to maintain the well-being of these 84 1 subjects." And that's important. 2 In our proposal for whether or not a 3 monitoring procedure can be acceptable as a direct 4 benefit, any benefit of monitoring must be an 5 objective of the study. For approval under 46.405, 6 the monitoring procedures must have the intended, not 7 the incidental, potential benefit of influencing the 8 child's management of the disease. And we have a 9 rationale and some examples to make clear what we're 10 talking about. 11 Protection of pediatric subjects should 12 discourage piggybacking greater than minimal risk 13 procedures into treatment trials if these procedures 14 do not, in and of themselves, have a prospect for 15 direct benefit or the procedure's efficacy is not a 16 focus of the research. 17 Now, it seems to me we are assuming a 18 component analysis here. I mean, what we're really 19 saying is you may doing an intervention study, to 20 which there is direct benefit, but if the monitoring 21 procedures are an add-on that are greater than minimal 22 risk, you can't call that direct benefit simply 85 1 because your intervention is a direct benefit. You 2 have to demonstrate that those monitoring procedures 3 have a direct benefit, otherwise they have to be 4 evaluated under 406 or 407. 5 So, here's an example. A research study 6 uses conscious sedation -- this is a study where it's 7 not an intervention study, but the researchers are 8 arguing that the monitoring procedure itself provides 9 direct benefit. A research study uses conscious 10 sedation and an MRI to study basic brain activity in 11 children with ADHD. The investigator states that the 12 MRI has direct benefit because, in some children, he 13 or she may discover a nascent tumor. 14 This monitoring procedure would not be 15 approvable under 405 because evaluating a technique to 16 detect tumors is not the intent of the research, an 17 MRI is not used in standard practice to detect nascent 18 tumors, and there's not evidence that children with 19 ADHD are prone to such tumors. 20 Okay. So, then we go to applying 405 21 recommendations to Phase I study. And I know there's 22 going to be a lot of discussion on all of these. We 86 1 know that. So this is a beginning. 2 What are Phase I studies? We took some 3 definitions, for example, from CIOMS. Phase I refers 4 to the first introduction of a drug into humans. 5 Normal volunteer subjects are usually studied to 6 determine levels of drugs at which toxicity is 7 observed. Such studies are followed by dose ranging 8 studies in patients for safety and, in some cases, 9 early evidence of effectiveness. 10 Now, the SRIC pointed out that for some 11 pediatric illnesses, like cancer, patients, rather 12 than normal volunteer subjects, are usually studied in 13 Phase I. 14 Can Phase I drug studies with pediatric 15 patients be approved under a 405? If you're measuring 16 for levels of toxicity, can you ever say that there's 17 a potential of direct benefit? And the problem is 18 that the Phase I study is not designed or intended to 19 test direct benefit. This is difficult to estimate, 20 if you're doing a risk benefit, because the absolute 21 level of acceptable toxicity is the purpose of the 22 study. You may have animal studies or adult studies, 87 1 but you're doing it in children because you believe 2 their metabolism is different or whatever. 3 Sometimes previous studies on animals or 4 adults are not valid for pediatric populations, and at 5 the same time, there is a documented benefit of Phase 6 I studies that sometimes occur but the range is 7 typically low, from five to ten percent. Sometimes, 8 for example, a tumor maybe may shrink, or something 9 may happen when you're testing for the toxicity. 10 So, we have to be very cautious because 11 this could be a benefit. But, at the same time, one 12 wants to be cautious about it. So, many pediatric 13 Phase I studies pose greater than a minor increase 14 over minimal risk and, thus, cannot be approved under 15 406. So, they either have to go to a 407 or be 16 approved under a 405. And we certainly do not want 17 investigators pushing research into a 405 simply 18 because they don't want to go to a 407. I think that 19 what SACHRP has done with the 407 process, the 20 streamlining it, hopefully will encourage IRBs, when 21 appropriate, to use that mechanism, but we still know 22 there's fears on the part of investigators to go that 88 1 route. 2 So, our recommendation is trying to allow 3 IRBs flexibility to approve a Phase I study under 405 4 but setting -- but being somewhat conservative in 5 criteria that should be used. So, to be approved 6 under 405, Phase I studies must satisfy the same 7 criteria recommended for all 405 classifications. 8 The prospect of direct benefit to the subject must be 9 proportional to the probability and magnitude of risk. 10 Even if the risks are balanced by anticipated -- I 11 don't know why I have evidence there -- by anticipated 12 benefit, a Phase I study may not be approved under 405 13 if the anticipated benefits are not at least as 14 favorable to the subjects as available alternative 15 approaches. And any benefit of a monitoring 16 procedure, simply because you're putting the -- you 17 know, you're testing for toxicity but you'll be 18 monitoring the tumor, let's say, it has to be an 19 objective of the study, that is, that the objective is 20 that it may improve treatment or diagnosis of the 21 child. It can't be just, maybe it will. 22 Okay. PIs should have the burden of 89 1 demonstrating that a Phase I trial qualifies under 405 2 and provide evidence and relevant prior studies. So, 3 the first part of this is actually getting to some of 4 the concerns that Felix is worrying about. I don't 5 think they do educate, somewhat, investigators, but 6 you know, you're issue is much broader. But the PIs 7 are responsible for defending, in some sense, in 8 providing justification if they want, under a 405, why 9 they believe the dosages selected would have the 10 potential for direct benefit, how that relates to the 11 characteristics of that particular subject population, 12 the prospect of direct benefit to the participating 13 subjects, and that the proposed direct benefit is 14 balanced by the potential risks. All of that is 15 required under 405 but what we're really saying here 16 is that investigators have to provide evidence. 17 Additional protections. To approve a 18 Phase I drug study under 405, IRBs should also 19 consider whether the risk benefit balance is 20 accurately reflected in the consent documents, that 21 recruitment does not offer inappropriate 22 incentivization for children and families, and that 90 1 collateral benefits of monitoring are calculated in 2 relation to the subject inclusion criteria and 3 disorder being studied. 4 So, basically, we don't want parents that 5 may be in -- have their children in treatment, or 6 let's say cancer protocols or other kinds of 7 protocols. We want to make sure that their 8 participation in Phase I are voluntary and that it is 9 clear the limits of the potential risks -- potential 10 benefits. 11 Here's an example. A Phase I pediatric 12 cancer protocol presenting greater than minor increase 13 over minimal risk, toxicity is estimated from pre- 14 clinical and adult studies, presents a very small 15 probability of direct benefit, 6 to 10 percent 16 probability of benefit through tumor shrinkage 17 associated with long-term survival. So this may have 18 been -- the evidence may have come from the animal or 19 adult studies. 20 This study could be approved under 405 for 21 children with cancer who are non-responders to 22 currently available treatments. For these children, 91 1 for whom there is no available alternative procedure, 2 the benefit would have to be proportional to the 3 probability and magnitude of the risk. 4 So, the alternative -- the available 5 treatments is handled here in the sense that these are 6 non-responders to available treatment. So, available 7 treatments are out there, but we already know this 8 population has not responded to them. 9 And one of the issues is that many parents 10 of ill children do not want Phase I studies to be 11 precluded from direct benefit. So we want to permit 12 that slight hope for children in those situations and, 13 at the same time, be conservative and make sure those 14 families are not exploited. 15 This is an example of a Phase I study that 16 would not be approved. A Phase I pediatric cancer 17 protocol presenting no more than a minor increase over 18 minimal risk of toxicity, as estimated from 19 preclinical and adult studies, will give a level 20 dosage with no probability of ameliorating the 21 subject's disease or disease management. The research 22 would not be approvable under 405. It could be 92 1 approvable under 406, if it met the 406 criteria. 2 Now, we felt it was important to look at 3 pediatric Phase I vaccine trials separately from Phase 4 I trials because it's really so different in the sense 5 that you're trying to prevent something, rather than - 6 - so the direct benefit is the prevention of the 7 disease or the mitigation, you know, of the disease. 8 So, we wanted to look at that separately. 9 So, Phase I in vaccine development refers 10 to the first introduction of a candidate vaccine into 11 a human population for initial determination of its 12 safety and biological effects including 13 immunogenicity. This phase may include studies of 14 dose and route of administration and usually involves 15 fewer than 100 volunteers. That's the CIOMS 16 definition. 17 Okay. So, just some issues. Research -- 18 vaccine trials are research with potential for saving 19 the lives of large numbers of children. Vaccines 20 produced from such trials in the past have saved more 21 lives and benefitted more children than many other 22 types of treatment studies. They must be conducted 93 1 with children because of childhood specific disorders 2 not typically found in adults and because children are 3 physiologically different from adults. 4 So what are the additional protections? 5 To approve -- oh, this should be to approve a Phase I 6 vaccine study. Under 405, in addition to criteria 7 under recommendations four and five, IRB should also 8 consider the benefits demonstrated by related studies, 9 the risk of contracting the disease under 10 investigation because, if there's not a great risk, 11 then the benefits are less, if there's not a great 12 risk of getting the disease. The dosage 13 justifications provided by the PI in terms of the 14 immunological susceptibility of the participants and 15 no participant should deliberately be subjected to the 16 illness under study. Yes. I feel like saying duh. 17 But, anyhow. 18 All right. Then, I think we need to get 19 to component analysis because all of this is so much 20 tied together. We know that this a lot. This is for 21 discussion. You know, having approval of any of these 22 is not a requirement for this. Okay. 94 1 CHAIR PRENTICE: Could we have five 2 minutes? 3 MEMBER FISHER: Oh, definitely. I would-- 4 CHAIR PRENTICE: We need a break, so -- 5 MEMBER FISHER: I would love five minutes. 6 CHAIR PRENTICE: -- bear that in mind as 7 you decide how you want to progress. 8 MEMBER FISHER: Are we having five minutes 9 now? 10 CHAIR PRENTICE: We have five minutes 11 before the scheduled break. 12 MEMBER FISHER: Oh, okay. All right. 13 Component analysis. What is it? To 14 determine the overall acceptability of the -- this is 15 from the National Commission -- and just to remind 16 you, I have a slide on it, but we did approve 17 component analysis. But at the last meeting, and at 18 meetings before, what was brought up was how is 19 component analysis applied? And so we tried to begin 20 to flesh that out to the group. 21 To determine the overall acceptability of 22 the research, the risk, and anticipated benefit of 95 1 activities described in a protocol, must be evaluated 2 individually, as well as collectively, as is done in 3 clinical practice. 4 NBAC recommended IRBs should assess the 5 potential harms and benefits of each intervention or 6 procedure in a pediatric protocol. The potential 7 benefits from one component of the research should not 8 be held to offset or justify the risks presented by 9 another. And our recommendation, that's approved by 10 SACHRP, is each research procedure in a study must be 11 evaluated independently in terms of potential benefits 12 and risks to subjects. Different procedures in a 13 single trial may be approved or disapproved under 14 different subpart D categories. So, there's a long 15 history of component analysis. 16 And nobody knows what I mean. Okay. So, 17 we wanted to give a case and Skip Nelson and Ernie, we 18 drew upon some of the work that they had done in this 19 area. 20 An investigation is provided sufficient 21 evidence that a protocol evaluating a new regimented 22 drug to treat renal transplant patients has a prospect 96 1 of direct benefit approvable under 405. The proposed 2 monitoring procedure requires two additional kidney 3 biopsies, posing greater than minimal risk. Now, 4 remember, these are two additional. It's not 5 approvable under 405 because there's no scientific 6 evidence or rationale that the biopsies, these two 7 extra ones, are going to contribute to the diagnosis 8 or treatment of the subjects' disease. So, therefore, 9 the biopsies must be approved, these additional ones, 10 must be approved under 406 or 407 under a component 11 analysis. 12 A potentially approvable one would be 13 extra biopsies could help determine at an earlier 14 stage whether rejection is occurring. In this 15 context, the IRB must determine whether the risks of 16 the two additional biopsies are outweighed by the 17 anticipated benefits. So, there is a probability that 18 it could help with diagnosis. It still has to be, the 19 criteria of 405 still has to be applied. That is, are 20 the risks balanced by the benefits of these two extra 21 biopsies? 22 For example, there may be no evidentiary 97 1 basis to assume a rejection in this population or 2 ordinary testing, available procedures that are the 3 standard of care will identify rejection, if it 4 exists, in a timely fashion. So, it doesn't satisfy 5 405 because there are alternatives out there that are 6 less risky. Just because a small potential benefit 7 can be identified, does not mean it balances the risk. 8 SACHRP may wish to clarify how component 9 analysis applies to pre-randomization and post- 10 randomization. What does that mean? Risks of 11 research procedures used in intervention as well as 12 controlled groups -- oh, I'm sorry. This is just what 13 we're going to do and then I'm going to say what it 14 means. The ability to receive intervention at the end 15 of the trial and symptom management. 16 Now, component analysis in intervention 17 trials with multiple arms. So, this has the issue to 18 do with if a component analysis says that if you have 19 two or more arms of an intervention study, you need to 20 evaluate each arm in terms of 405 criteria. That 21 simply what component analysis is saying. So, it 22 could be two experimental treatments, it could be an 98 1 experimental and a no treatment control, it could be 2 a placebo. 3 Pre- and post-randomization analysis. 4 Pre-randomization analysis. Also, I don't know, 5 Ernie, if you coined this term collective analysis, 6 but it was used in your work. Potential direct 7 subject benefit that is associated with one 8 intervention is used to justify the risks of the other 9 intervention. So, for example, if you're in a no 10 treatment control group, if half of the subjects are 11 going to be randomly assigned to a no treatment 12 control group and half to the intervention, there's no 13 probability of direct benefit in the no treatment 14 control, but in a pre-randomization analysis, one can 15 say that there's a 50 percent probability of being in 16 the intervention study which has benefit. Okay? That 17 would be collectively looking at the risk benefit. 18 Post-randomization is that you actually do 19 separate analysis on the risks and benefits of being 20 in each. And it could be that the no treatment 21 control needs to be approved under a 404, or 406, or 22 a 407 because it may not provide any direct benefit. 99 1 Or, it may have monitoring procedures that could be 2 used for diagnosis and, therefore, is evaluated under 3 405 but using different information. 4 So, okay. Here's an example of a placebo 5 control trial. A protocol intends to study the effect 6 of a biosynthetic growth hormone to promote growth in 7 children with Turner's Syndrome. Children will be 8 randomly assigned to subcutaneous injection of either 9 the biosynthetic agent or placebo saline solution 10 three days per week for several months. 11 If one used pre-randomization collective 12 analysis, each child has a 50-50 chance of being 13 assigned to the active study arrangement. If there's 14 adequate evidence of the probability of direct benefit 15 of the agent over available alternative procedures, 16 the study might be approved under 405. 17 If you're using a post-randomization 18 component analysis, the agent and the placebo arm are 19 analyzed separately. There's no probability of direct 20 benefit for children participating in the placebo arm. 21 The placebo arm must be approved under 404, 406, and 22 407. 100 1 Recommendation one -- 2 CHAIR PRENTICE: Celia? 3 MEMBER FISHER: Yes? 4 CHAIR PRENTICE: I would suggest that we 5 take a break -- 6 MEMBER FISHER: Sure. 7 CHAIR PRENTICE: -- and that you do the 8 recommendations after the break. 9 MEMBER FISHER: Good idea. 10 CHAIR PRENTICE: All right. Fifteen 11 minutes, folks, please. 12 (Whereupon the foregoing meeting went off 13 the record at 10:33 a.m. and went back on the record 14 at 10:53 a.m.) 15 CHAIR PRENTICE: Okay. All right. Are we 16 ready? Let's begin. 17 MEMBER KORNETSKY: Okay. 18 CHAIR PRENTICE: Why don't you indicate 19 the change in the program. 20 MEMBER KORNETSKY: Do we -- are there 21 people -- let me go see who is back there. 22 Okay. We are going to get started. We 101 1 gave some thought about how to proceed because I know 2 what we just presented is going provoke lots of 3 discussion, which it should. And so we talked with 4 Ernie about how we want to proceed. 5 We're going to move ahead with a 6 discussion about wards of the state, which I think, 7 hopefully, will be a little bit more concrete and not 8 as abstract. And then, if we have time, go back to 9 some of the discussion for input from our members from 10 SACHRP. 11 So, the first thing I want to just say is 12 that it wasn't planned this way, but I think it is 13 very, very timely, this is probably one of the more 14 timely discussions that SACHRP is having. 15 If any of you have visited the OHRP 16 website and the most recent determination letters, 17 there was recently a compliance investigation 18 specifically around the issue of wards. And there are 19 probably anywhere from 15 to 17 letters to 20 institutions throughout the United States about wards 21 and about the ward regulation. 22 And I just want to read for you, I didn't 102 1 have a slide, just a segment from one of the letters 2 to demonstrate that this is timely, the findings OHRP 3 found that when reviewing the research, the IRB failed 4 to obtain sufficient information to made 5 determinations required for the approval of research 6 under regulations. OHRP found IRB records for the 7 above referenced research demonstrated a failure of 8 the IRB to obtain sufficient information regarding the 9 selection of wards of the state and foster children as 10 research subjects. OHRP found IRB records for the 11 above referenced research demonstrated a failure of 12 the IRB to obtain sufficient information regarding the 13 process for obtaining permission of parents or 14 guardians for wards of the state or foster children. 15 OHRP found IRB records for the above referenced 16 research demonstrated a failure of the IRB to obtain 17 sufficient information regarding safeguards with the 18 respect to enrollment of wards of the state and foster 19 children. 20 So, this is very, very timely. The 21 regulations have not changed. This section of the 22 regulations, 409, has been there for some time. I 103 1 think it's been sort of one of the sleeper parts that 2 we just have not spent a lot of attention to and 3 deserves some discussion. So, at our last 4 subcommittee meeting, we went through this and tried 5 to give some ideas and guidance on how to proceed. 6 The regulations are very, very short in 7 this respect. And I have put up here what the 8 regulations say. There's really two parts that deal 9 with wards. What is says is that if you're ward of 10 the state, or any other agency, or institution or 11 entity, you can be included in research under 406 and 12 407. And that's a reminder that this, specifically, 13 is research, that it's greater than minimal risk with 14 no benefit. Okay? This is not all research that 15 involves wards. This is specifically research that 16 involves greater than minimal risk and no benefit. 17 The only way you can be included is if the research is 18 dealing with their status as a ward, that that's the 19 purpose of the research and that's why you're studying 20 them or if the research is conducted in facilities, 21 schools, camps, where a majority of the children 22 involved are not wards. So, that would be the first 104 1 condition that would need to be satisfied. 2 The second part of the regulation then 3 goes on to say that if you are approving, if you can 4 meet one of those two criteria, that the IRB then is 5 required to appoint an advocate for each child who is 6 a ward, in addition to any other individuals who may 7 be acting in behalf of the child as a guardian or in 8 loco parentis. The regulations specify that the 9 individual can serve as an advocate for more than one 10 child. So, you could have an advocate that would 11 serve for a group of wards. The advocate shall be an 12 individual who has background and experience to act 13 in, agrees to act in the best interest of the child, 14 for the duration of the child's participation in the 15 research. So, this is, obviously, not just limited to 16 the decision of whether to participate or not. This 17 is for the entire period that that ward is in the 18 state. And that the advocate is not associated in 19 any way, except as a role or advocate or member of the 20 IRB, with the research, the investigators, or the 21 guardian organization. 22 So, this is really the thrust. This is 105 1 the limit of what the regs say. And there's lots of 2 room for IRBs to have lots of questions about, you 3 know, how to apply this. 4 Oh, there's one other section. This is -- 5 what we're referring to here is even though the ward 6 part, 409, refers to research that involves greater 7 than minimal risk and no benefit, if you go back to 8 subpart A, this is language that is familiar to 9 everyone, what this is basically saying, is when you 10 have a vulnerable population, you need to have extra 11 protections. 12 So, we can question ourselves, and I think 13 we can easily answer that, even if you are a ward and 14 potentially benefit, research that potentially has a 15 benefit, would you be considered a vulnerable 16 population that requires extra protections and what 17 would they be? 18 So, we didn't -- we looked at wards in 19 general, as a group, whether they're in research that 20 they'll benefit and when they won't, and thought about 21 conceptually, what are the issues, what are the 22 problems and how can we protect them as we are 106 1 required to in 409 and as we are given guidance to 2 think about in subpart A. 3 Just a couple of relevant definitions. 4 I'm not going to go through these. There's a 5 definition for permission, there's a definition for 6 parents, there's a definition for guardian. Advocate 7 is not defined and we'll talk a little bit about that. 8 And it's interesting, ward is actually not defined in 9 HHS regulations, but it is defined in FDA regulations. 10 And, to remind you, that FDA has recently, within the 11 last couple of years, adopted a subpart D, which 12 includes the ward's provision and they do have a 13 definition. 14 So, before we think about regulatory-wise, 15 I'd like to take a step back and think about well, 16 what are the issues? What are the practical issues? 17 What are the things that you would just genuinely 18 concern yourselves about in thinking about involving 19 wards in research. And I think a couple of things, 20 before we think about how to consider these things 21 within guidance or regulations is that when a child is 22 a ward of the state, it's important to remember that 107 1 their physical custody, who takes care of them, who 2 brings them to the doctor, who brings them for their 3 services, may be very different from the legal 4 custody. Okay, so there's a disconnect there of where 5 that child physically is, who may know that child, is 6 working with that child, and who actually has legal 7 authority. And the legally recognized guardian may 8 not be involved at all in the day-to-day care of the 9 child. The state usually is and sometimes there is a 10 social worker or a worker who has a case assigned, but 11 that child may be in a foster care situation. 12 There are all different types of 13 arrangements for decision making. And I know when I 14 get any questions from my own investigators about 15 people coming in and who is the guardian and whatever, 16 very, very complicated. It's complicated by state and 17 by individuals. There are different arrangements 18 regarding decision making. When a child is in foster 19 care, that doesn't automatically mean that parental 20 rights have been removed. In some cases, biological 21 parents still have legal authority to make decisions 22 or the state may have legal authority. The IRB is not 108 1 going to know that and probably the investigator isn't 2 going to know that easily as well. I mean, that 3 usually requires looking at some legal documentation. 4 So, you know, the term ward and what it means and 5 foster care really is very, very specific and there 6 are different requirements, as far as decision making. 7 There are frequent fluctuations in 8 guardianship. I mean, if you think about how this 9 impacts an individual who is in research, they're 10 going from foster home to foster home. They may be a 11 ward of the state and then the parental rights may be 12 reinstated and they may become a ward of the state 13 again. This is very, very common in the population. 14 They are transient and that results in transient 15 relationships with guardians and people who are making 16 decisions. There are variants among state 17 regulations, if any exist. And really, I think that, 18 in thinking about all of this, it's very important to 19 think that the safety of the ward while involved in 20 research requires appropriate oversight, appointment 21 follows which may become difficult and complicated 22 with a ward. So, this is the problem of thinking 109 1 about how to involve wards in research and how we can 2 best protect them. 3 Some other things are, and think about, 4 are all wards vulnerable, not just those subjected to 5 greater than minimal risk research with no prospect of 6 direct benefit? And that's why I called your 7 attention to subpart A talking about vulnerable 8 populations, reminding you again, 409 is just greater 9 than minimal risk with no direct benefit. But I think 10 you can be easily convinced by the issues that I just 11 put on the table that, even when there is potential 12 for direct benefit and it is a therapeutic trial, that 13 they are vulnerable for all of those reasons that we 14 just presented. And, therefore, should extra 15 protections be implemented for any ward, regardless of 16 the type of research and, if so, what they should be. 17 The goals of the guidance, as we went 18 through this, is, obviously, that we want to avoid 19 exploitation of wards as vulnerable population. We 20 want to also assure that wards are not excluded as 21 beneficiaries of research just because they are wards, 22 especially if it offers the potential for direct 110 1 benefit, and to assure continuity of care, safety, and 2 oversight of research for wards while involved in 3 research, and guardianship and physical location 4 changes. So, these were sort of the principles that 5 we thought about that, in any type of guidance, in 6 what we wanted to recommend. 7 So, I'm going to go through the 8 recommendations and then we can come back to them, 9 individually. 10 Recommendation one is really, I think, 11 just trying to synchronize again FDA and HHS 12 regulations. It makes sense that there is a 13 definition of a ward. We are recommending that the 14 definition that the FDA uses seems reasonable, seems 15 like it would apply in any situation, and the first 16 recommendation is that HHS should adopt this and that 17 we should recognize this as part of our definitions. 18 Recommendation two. We started to think 19 about the issue of well, who should be an advocate? 20 How should we appoint an advocate? And thinking, 21 again, of some of the principles that we were thinking 22 about. 111 1 So, to give some guidance to IRBs that if 2 they do need to appoint an advocate, that the IRB 3 should take into consideration the following regarding 4 the advocacy roles. These are things to help them 5 figure out who might be an appropriate person. 6 The advocate should have appropriate 7 qualifications in order to take into consideration the 8 nature of the research and understanding of the 9 advocacy roles. Okay, someone really needs to 10 understand what an advocacy role is and have that -- 11 have the qualifications to do that. We don't want to, 12 again, get too prescriptive, that, you know, this A 13 type of person can or can't be. Sometimes this may 14 just be individual personal characteristics, or their 15 background, or maybe they took care of foster 16 children. So, again, we're trying to give some 17 guidance but not be really prescriptive. 18 Have appropriate time to commit to the 19 expected ongoing role, including meeting with each 20 ward, care givers and researchers. And this really is 21 just, it's not a one time, should the ward be or not 22 be, this is ongoing. And that becomes important again 112 1 as changes and fluctuations in guardianship change. 2 Is the child in a different situation that, you know, 3 that there are different safety issues now? Can they 4 make their appointments? Are they physically remote, 5 you know, removed from the facility? So, someone 6 needs to have the time to be able to do that. 7 Have the ability to make a decision 8 regarding each ward's participation in the research, 9 that is autonomous and independent of any contractual 10 requirements concerning the number or types of 11 subjects to be enrolled. This came up because there 12 was a discussion of well, can you pay someone to be an 13 advocate. This is a lot of time, can you pay them to 14 do it? And sort of, what's the connection, to try to 15 review any conflicts of interest, that they feel 16 pressured because this study involves so many people, 17 to keep that person in the research. And there can be 18 other types of relations. So this is really just 19 recognizing that it needs to be autonomous. This 20 person needs to feel free and not be tied to any 21 decision that they have to convince that ward that 22 it's in their best interest to, you know, continue in 113 1 the research, when it may not be. 2 They should have independence from the 3 research for the entire period of the advocacy role. 4 Okay? They really, they shouldn't, it shouldn't 5 necessarily be a member of the research team, it 6 shouldn't be a social worker that happens to be 7 working on that team, if they have a role in that 8 research, and they have to really become familiar with 9 the child's health, behavior, social, physical 10 environment, and act as a neutral intermediary between 11 the child and the research efforts. Again, 12 understanding what their role is. 13 So, those were some of the principles and 14 guiding factors that we think would be helpful for 15 IRBs to think about when they do come to the point 16 that they need to appoint an advocate. 17 Now, we thought about, you know, although 18 it's not required by the regulations, this is the 19 issue, you have a ward, a recognized ward, and perhaps 20 they are in a therapeutic beneficial trial. Okay, the 21 regulations don't require that an advocate be 22 appointed, but in thinking, again, if you think 114 1 through that list of issues, those issues apply 2 whether you're in beneficial or non-beneficial 3 research, that we thought that we wanted to make the 4 recommendation that the IRB should consider, not that 5 they must, not to be prescriptive, that they should 6 consider appointing an advocate for wards of state 7 participating in research approved under 404 and 405. 8 Okay? 9 And we may have some discussion. I mean, 10 this is, again, it's a consideration, it's not a 11 requirement. One of our subcommittee members actually 12 was involved in some of the early HIV trials and just 13 as an ethical principle in thinking about how to 14 safely enroll these children in some of trial, did 15 exactly this. Did exactly this because they felt that 16 was the right thing to do in those situations, not 17 because the regulations required it. And I think that 18 was the thinking that we've really felt that this, you 19 know, should be considered, you know, the right thing 20 to do. It may not pertain to all different research, 21 but certainly there is a category that it would. 22 The other things is really to make it 115 1 clear that children can be involved in research and 2 then become wards of the state. And, if an individual 3 or adolescent becomes a ward during the course of the 4 research, that these requirements kick in. Okay? 5 Something has changed. Their parents are no longer 6 making their decisions, where they live, who they go 7 to, who they see, where they're getting their support 8 changes and that these requirements should be 9 implemented. And this includes an appointment of an 10 advocate to determine that it is appropriate for the 11 ward to continue research participation and then to 12 continue to serve that intermediary role, as the 13 research progresses. 14 And really, the rationale here is when a 15 child becomes a ward of the state, the legally 16 recognized decision maker may change. Informed 17 consent is an ongoing process, okay? It's not a one 18 time thing and, as a result, the logistics of who 19 decides and the implications of the research 20 participation may also change. 21 Now, recommendation five is just sort of 22 a heads up type of thing. I think, again, we don't 116 1 want to be disruptive to research. This does require 2 an amount of work when you have to appoint an 3 advocate. But, to encourage investigators who work 4 with research populations where there is a higher 5 chance or there is a reasonable possibility that 6 subjects may become wards. This is sort of a higher 7 risk for becoming wards population, that during the 8 course of the research, that the IRB and the 9 investigator should think about this up front so that 10 you have everything set up. So, you might want to 11 consider thinking about who would serve that potential 12 advocate role so once a child becomes an advocate, 13 you're all set, you don't have to, you know, delay the 14 research. 15 And, again, the effort is to reduce 16 unnecessary delays or interruptions in research and, 17 importantly, also the subject's participation. 18 Recommendation number six, I think, is 19 probably one of the most important recommendations and 20 I have found the most problematic area. And, really, 21 it's an educative role. 22 In many situations, you can't predict when 117 1 someone's going to walk in the door and be a ward of 2 the state and you want to enroll them in research. 3 And it's really important to get the message out, you 4 know. I say to our investigators, you know, you hear 5 the word ward, you call our office. You know, I mean, 6 that's the message that has to be given. No matter 7 what, just call. 8 And so, IRBs really need to work in 9 collaboration with their institutions, legal counsel's 10 office, because many times the call goes to legal 11 counsel. You know, so and so is here with a piece of 12 paper that says x, y, and z, can they consent, can 13 they be enrolled. So, legal counsel often gets those 14 calls. 15 But that you should really provide 16 guidance and education to investigators and their 17 associated research personnel regarding who is defined 18 as the ward. You need to notify the IRB when it's 19 being considered, and the need to notify the IRB when 20 a child or adolescent already participating in 21 research becomes a ward of the state. And this is an 22 ongoing process. 118 1 And we're trying, you know, we send out 2 newsletters every so often, you know, just a reminder, 3 you hear the word ward of the state, call our office. 4 Number seven gets to, we started to talk 5 about component analysis. I think we can probably 6 think about this outside of a complicated discussion. 7 But what this really says is that if you do do 8 component analysis, you know, again, there's the 9 regulatory part if it's greater than minimal risk and 10 no benefit, that if you do component analysis, and you 11 come up with, in a particular study, two different, 12 you know, two different arms, that the most 13 restrictive has to apply. And so, that means if 14 you're going to enroll a ward of the state in that 15 part of the protocol, that you would need to follow 16 the provisions of 409. 17 Component analysis applies to all 18 pediatric research and, therefore, it's part of the 19 protocol, it fits into the criteria of 406 or 407. 20 And, you know, you just need to remember that if 21 something falls on that side of 406 or 407 and you're 22 going to involve a ward of the state, you've got to 119 1 enact the ward regulations. 2 So, that is the sort of presentation of 3 the different recommendations and guidance that we've 4 offered. Again, I think it's very, very timely, and 5 I'll hand it over to you, Ernie. 6 CHAIR PRENTICE: Thanks, Susan. We'll 7 follow the previous procedure. We'll look at each 8 recommendation in sequence. 9 We are now on recommendation number one. 10 Questions? Discussion? Yes, Nancy? 11 MEMBER JONES: Can I ask, first just a 12 more general, in showing my naivety, but as we have an 13 international panel coming up in the second half, it 14 sort of tunes me into, you know, are the same kinds of 15 considerations like, Susan, you talked about an HIV 16 trial and I know a lot of participants may end up 17 being an orphan, and I don't know if the same kind of 18 term of wards is applicable, you know, as we start to 19 think out of the sphere nationally. You know, can you 20 enroll orphans that may not be true wards? Or are -- 21 I guess I'm asking -- 22 MEMBER FISHER: How this applies 120 1 internationally? 2 MEMBER JONES: Yes. 3 MEMBER KORNETSKY: It's a really good 4 question. I don't have the expertise in that area. 5 We have an international panel this afternoon. I 6 think it would be a very important question. Celia, 7 do you have? 8 MEMBER FISHER: No. I don't know how to 9 answer that, but I would say it shouldn't stop us from 10 approving harmonization with FDA, although, because we 11 are trying to interpret language, ward, which is used 12 in the regs. I do think that whether guidance would 13 suggest, for example, that children without legal 14 guardians who are also not considered emancipated, or 15 in other situations, the wards, IRB should consider 16 applying the wards. I think that's an excellent point 17 for discussions this afternoon. 18 CHAIR PRENTICE: I think that there is 19 probably some flexibility in the definition. A child 20 who is placed in the legal custody of the state or 21 other agency, institution, or entity consistent with 22 applicable federal, state, or local law. There may be 121 1 no applicable laws. So, I don't think this precludes 2 the, you know, the application of this particular 3 definition to research involving the subject 4 population, you know, you're talking about. 5 But, again, as Susan certainly indicated, 6 we need to look at these definitions as they exist in 7 subpart D. And we can, perhaps, we'll have a lot of 8 time for discussion this afternoon. I would invite 9 you to bring that issue up. 10 MEMBER KORNETSKY: I can definitely see it 11 being quite a challenge, internationally. 12 CHAIR PRENTICE: All right. Other 13 discussion with regard to recommendation number one? 14 Felix? 15 MEMBER GYI: Again, just, this may be 16 along the lines of a general discussion but, you know, 17 recently, within the last year, there were some 18 determination letters that were issued and some, I 19 think there were even some congressional hearings 20 relating to involvement of wards and HIV Aids trial. 21 I don't recall the details, but I wonder if there's 22 somebody, whether it's you or somebody else, that 122 1 might help us to understand what those issues are so 2 that we can factor that into our own thinking as it 3 relates to commonization issues, as well as other 4 recommendations that are before us. 5 CHAIR PRENTICE: I know what you're 6 talking about, but I'm not in a position to comment 7 intelligently about the details of that. Perhaps 8 that's also something that could be brought up this 9 afternoon, because we are going to be talking about 10 a number of different issues in international research 11 and we're going to have, you know, a panel of experts 12 who can address those. 13 MEMBER KORNETSKY: Felix, you may have 14 come in late. All of those determination letters, I 15 mean, it may not talk about what prompted it, but all 16 of those determination letters, I actually read from 17 the determinations, are on the website now. They're 18 probably about 15 or 16 of them. I know many more 19 institutions were questioned, including our own. And 20 the conclusion that I reached from reading part of 21 the determination letters is that there was, you know, 22 this may not have been necessarily thought through and 123 1 applied in many situations. And that's very 2 consistent to seven, eight years ago, I'm thinking. 3 So -- 4 MEMBER FISHER: Yes. Just to, I think 5 what Susan's saying is is that the recommendations, as 6 articulated by Susan, would have been very helpful for 7 these cases that came up. That's very consistent with 8 what was seen as potentially noncompliance. 9 MEMBER KORNETSKY: We did these 10 recommendations before I saw the compliance letters. 11 MEMBER FISHER: But it's consistent. 12 MEMBER GYI: You factored it in? 13 MEMBER KORNETSKY: Yes. I mean, it was 14 factored into it. Yes. 15 CHAIR PRENTICE: Other questions, 16 comments? Motions? 17 MEMBER SELWITZ: I move acceptance of this 18 recommendation. 19 MEMBER POWE: And I could second. 20 CHAIR PRENTICE: Further discussion? 21 (No response.) 22 CHAIR PRENTICE: All those in favor? 124 1 (Unanimous show of hands.) 2 CHAIR PRENTICE: Any opposed? 3 (No response.) 4 CHAIR PRENTICE: Any abstentions? 5 (No response.) 6 CHAIR PRENTICE: The motion carries. 7 Recommendation number two is on the 8 screen. 9 MEMBER KORNETSKY: Ada Sue, we used your 10 take into consideration. 11 MEMBER FISHER: But also remember, there's 12 two other parts to this on the next slide. 13 CHAIR PRENTICE: Use the microphone. 14 MEMBER KORNETSKY: Celia said there's two 15 other parts that are on the next slide also that -- 16 MEMBER FISHER: And in some sense, the two 17 secondary points are really part of the third point on 18 this -- 19 MEMBER KORNETSKY: Right. 20 MEMBER FISHER: -- because it's really 21 further articulating what is said in the third point 22 about the independent and ongoing role of the 125 1 advocate. 2 CHAIR PRENTICE: Yes? Neil? 3 MEMBER POWE: Just regarding the third 4 bullet here, I guess the concept that this is trying 5 to impart is conflict of interest -- 6 MEMBER KORNETSKY: That's correct. 7 MEMBER POWE: -- by the advocate. I guess 8 what I was a little concerned about is that it's very 9 specific to concerning the number of types of subjects 10 to enroll. And it seems to me that the conflict of 11 interest is far greater than just the number of 12 subject to be enrolled. It's the maintenance of the 13 subjects in the study as comes up in later 14 recommendations. But I think it could be even more, 15 it's just more far reaching than that. You know, I 16 wonder if that's just too narrow, the ideas is 17 conflict of interest. 18 MEMBER FISHER: Yes, like recruitment, 19 maintenance -- 20 MEMBER KORNETSKY: So, your suggesting 21 adding some other things, just not -- 22 CHAIR PRENTICE: Yes. 126 1 MEMBER KORNETSKY: -- concerning the 2 number, types, recruitment, ongoing role and 3 relationship, to add -- 4 MEMBER POWE: Right. 5 MEMBER KORNETSKY: -- enrollment. Add 6 that in there, that it's -- I think that's a good 7 point. 8 CHAIR PRENTICE: I've noticed that as 9 well. What I might suggest as a starting point of 10 saying of any employment, comma, professional 11 relationship, or contractual requirements concerning 12 the number or types of subjects to be enrolled, at 13 least to get some language on the board. 14 MEMBER KORNETSKY: Okay. I'm sorry. You 15 want to -- 16 CHAIR PRENTICE: Yes. 17 MEMBER KORNETSKY: She's a much better 18 typer than me. 19 CHAIR PRENTICE: You can say, of any 20 employment, professional, you could say professional 21 or financial relationships, or contractual 22 requirements. 127 1 MEMBER FISHER: Where did you want 2 professional? Of any employment -- 3 CHAIR PRENTICE: Of any employment, comma, 4 professional or financial relationships -- 5 MEMBER KORNETSKY: Or contractual 6 requirements. 7 CHAIR PRENTICE: And then, or contractual 8 requirements concerning the number of and types of 9 subject to be enrolled, which sort of has everything 10 in there in terms of a potential conflict of interest. 11 MEMBER FISHER: Right. I would say for 12 Neil's point, subjects to be recruited, enrolled, and 13 maintained. Is that -- I mean, it could be managed, 14 but -- 15 CHAIR PRENTICE: Well, I wouldn't say 16 maintained. I don't think that's a good word. You 17 know, when you, I mean, it's implied when you recruit 18 people, you know, you're not going to coerce them into 19 continuing to participate. I'm not so sure you need 20 to really -- I mean, how much do you need to push 21 that? 22 MEMBER FISHER: Well, remember, informed 128 1 consent is supposed to be ongoing and children are 2 supposed to be free to withdraw at any time. So, some 3 kind of language -- 4 MEMBER KORNETSKY: I'm going oversight, 5 something along those lines. 6 CHAIR PRENTICE: All right. That would 7 work. 8 MEMBER FISHER: In ongoing participation? 9 MEMBER KORNETSKY: It's really ongoing -- 10 CHAIR PRENTICE: Enroll, recruit -- 11 MEMBER FISHER: No, no. Not on -- 12 UNIDENTIFIED SPEAKER: Ongoing -- 13 MEMBER KORNETSKY: Participation. I think 14 the only -- and I think doesn't prohibit. I think, 15 you know, the issue was that an advocate may likely be 16 an employee of the organization that's conducting the 17 research but they're independent. The issue was, if 18 you had an NIH grant, if you had a grant, I mean, this 19 hasn't come up, but the issue is if you had a grant 20 and wanted to put on the grant you wanted to pay 21 someone for their role as an advocate, whether that 22 should -- that was some of the discussion. I haven't 129 1 actually seen that applied, but I would rely on other 2 people to -- 3 CHAIR PRENTICE: Do you think that 4 inserting the word employment sort of implies that you 5 can't be employed by the institution conducting the 6 research? 7 MEMBER KORNETSKY: I mean, I don't think 8 so. I just want to make sure that it doesn't. 9 MEMBER SELWITZ: Can I ask a question 10 here? 11 CHAIR PRENTICE: Yes. 12 MEMBER SELWITZ: I mean, you know, PIs are 13 paid by the institution that employs them. 14 MEMBER FISHER: Yes, I -- 15 MEMBER SELWITZ: You know, I mean, I don't 16 think necessarily paying advocates is a bad thing. 17 MEMBER KORNETSKY: Right. 18 MEMBER SELWITZ: You want a quality 19 advocate. You want somebody to give you the time and 20 the effort. And if you're going to restrict people to 21 pay them for their time, you may have troubles finding 22 an individual that will voluntarily do what they want 130 1 to do. I also 100 percent concur there has to be 2 independence. I mean, that individual, even though 3 they're being paid, their payment, for example, is not 4 contingent upon how many people they enroll, which is 5 what I thought -- 6 MEMBER KORNETSKY: That's what they're 7 saying, that there's no sort of contractual, that 8 they're involvement is not contractually related to 9 that. And that's what -- 10 MEMBER SELWITZ: But you're not saying -- 11 MEMBER KORNETSKY: That's exactly the 12 point. 13 MEMBER SELWITZ: I mean, I don't object to 14 advocates being paid and that's not your intent. 15 MEMBER KORNETSKY: Right. 16 MEMBER SELWITZ: You intent is what is the 17 firewall? 18 MEMBER KORNETSKY: That is correct. 19 MEMBER SELWITZ: Okay. I just don't want 20 us to get -- 21 MEMBER FISHER: So, what I did was, I 22 think -- 131 1 MEMBER SELWITZ: -- to take it too far. 2 MEMBER FISHER: It does -- I agree with 3 you Ada Sue, I think employment does -- might be 4 perceived as too restrictive. So, what I did, see if 5 you like this, an independent under contractual 6 requirements or financial gains -- 7 MEMBER KORNETSKY: Concerning the number, 8 types of subject -- 9 MEMBER FISHER: Types of subjects required 10 for recruitment, enrollment and ongoing participation. 11 MEMBER JONES: I know probably down to the 12 point of the word smithing, but I liked what Neil had 13 to say about what the point was, that you want to 14 avoid conflicts of interest. 15 CHAIR PRENTICE: How about -- 16 MEMBER JONES: So, do we have to be so 17 much listing as rather than communicating what the 18 concept is that you want them to be able to make a 19 decision regarding each ward's -- 20 MEMBER KORNETSKY: We need to give some 21 guidance as to how a conflict of interest could 22 potentially be interpreted here. I think just saying 132 1 what a conflict of interest, you know, is -- 2 MEMBER FISHER: And it's very specific to 3 the participation. 4 CHAIR PRENTICE: Could you say 5 independent of any contractual requirements, comma, 6 financial gains, or other conflicts of interest? 7 MEMBER KORNETSKY: You could put that in, 8 yes. I think may get to Neil's point. 9 CHAIR PRENTICE: Would that get closer to 10 what you're talking about, Neil? 11 CHAIR PRENTICE: Could you try to insert 12 that with what's in there?MEMBER POWE: Yes. Yes, I 13 think we're getting better all the time. 14 (Laughter.) 15 MEMBER FISHER: You see the only problem - 16 - Oh, I'm sorry. The only problem I ask about is a 17 conflict is it that -- conflicts of interest can be 18 resolved. I'm just wondering whether or not 19 autonomous and independent of a conflict of interest 20 makes as much sense as autonomous and independent from 21 contractual requirements and financial gains. You 22 know -- 133 1 MEMBER SELWITZ: I don't know. And I 2 always get nervous when we sit here and start writing 3 -- 4 MEMBER FISHER: Yes. 5 MEMBER SELWITZ: -- in our great wisdom 6 and then we go home and we read what we wrote and we 7 think, you know, why did we change it or have we made 8 it better or made it worse. I always get nervous when 9 we do it onsite. 10 CHAIR PRENTICE: Isn't that always the 11 case? 12 MEMBER SELWITZ: Yes, yes. But, just I 13 mean -- 14 CHAIR PRENTICE: I know what you're 15 saying. 16 MEMBER SELWITZ: -- but I do. And I, 17 where I agree 100 percent with Neil, I don't feel 18 we're quite there yet on this particular language and 19 don't know if it wouldn't be better that we didn't 20 send the brilliant minds at the table off to think 21 about it, if you understand the concept, and come up. 22 Because I think we have to be -- I don't think we 134 1 should come up with something that is so restrictive 2 that we're putting restrictions there we don't mean. 3 I mean, the point is, if there is and, again, Neil, by 4 conflicts of interest, you were really tying that knot 5 just for any kind of conflict of interest, and so that 6 that advocate does need to be independent. All right? 7 But how do we say it in a way that -- 8 MEMBER FISHER: But can I just way what 9 the intent of this was? The intent was very, very 10 narrow. The intent was, basically, that people aren't 11 paid by the head. I mean, that was the intent of 12 this, that to further complicate it could create all 13 the problems, Ada Sue, that you spoke about before. 14 So, we really were. You know, an IRB can 15 use any other more conservative criteria. But we 16 really just wanted to make sure that, number one, PIs, 17 or grants, or settings, could pay this independent 18 advocate, because otherwise you'd never get one to be 19 so involved. And, number two, that that contract 20 that's made with them, if they're paid, would not be 21 by the head. That it wouldn't be determined by how 22 many people they permitted to be in this study, or 135 1 make them feel coerced not to have somebody withdraw. 2 And so, it was intended to be narrow, not broad. 3 CHAIR PRENTICE: Okay. Let me, at the 4 risk of trying to engage in word smithing, and in 5 consideration of Neil's comment, before you -- 6 MEMBER POWE: I think that this might 7 help. Suppose the advocate was the spouse of the 8 investigator, would that be a conflict? 9 CHAIR PRENTICE: Yes. 10 MEMBER POWE: Okay. I don't think that's 11 covered. 12 CHAIR PRENTICE: No. Here's what I'm 13 suggesting, and maybe what I'm going to suggest is 14 going to cover what you want and provide the 15 flexibility that Ada Sue -- 16 MEMBER FISHER: No. It says financial 17 gain, independent. 18 CHAIR PRENTICE: What? 19 MEMBER FISHER: I think it is covered, but 20 -- 21 CHAIR PRENTICE: Well, I'm not so sure it 22 is. But here, how about this? Have the ability to 136 1 make a decision regarding each ward's participation in 2 research that is, either use the word autonomous or 3 independent because I think they're pretty much the 4 same thing, that is autonomous and free of any 5 conflicts of interest. And let the IRB figure out 6 what a conflict of interest is and whether or not it 7 can be managed appropriately. 8 So that if, for example, the advocate is 9 a spouse of an investigator, I mean, you know, I would 10 call that a conflict of interest. Maybe somebody 11 might not think of it that way. Let the IRB figure it 12 out and not tie it to simply recruitment enrollment 13 and ongoing participation. 14 MEMBER FISHER: I think we should take it 15 back. 16 CHAIR PRENTICE: What? 17 MEMBER FISHER: I'm happy to take it back. 18 CHAIR PRENTICE: You want to take it back? 19 MEMBER FISHER: Well, I don't -- 20 CHAIR PRENTICE: Okay. 21 MEMBER FISHER: -- you know, I think we 22 understand the points. I think, you know, I think 137 1 it's important to see whether or not there's language 2 that includes conflicts of interest but is not so 3 overly restrictive that it just, you know, it becomes, 4 you know -- 5 MEMBER KORNETSKY: I mean -- yes. I think 6 that this was a detailed enough discussion that I 7 would feel uncomfortable just making changes without 8 the advisory committee. 9 CHAIR PRENTICE: Okay. 10 MEMBER KORNETSKY: They have lots to say 11 about this, so -- 12 CHAIR PRENTICE: Okay. Then, let's table 13 that and -- 14 MEMBER FISHER: But this is what we think 15 so far, that everybody's saying. 16 CHAIR PRENTICE: Yes, go ahead. 17 MEMBER POWE: I have one other comment 18 about bullet one. The word -- it's nice I think this 19 is guidance, but it says appropriate qualifications. 20 And, to me, it begs then what are appropriate 21 qualifications, begs that question. And I'm not 22 saying we need to go into details, but it just leaves 138 1 open to -- I don't know that we're providing any 2 guidance on appropriate qualifications from is 3 written. Do we need more guidance in that area? That 4 may be something else to take to the committee. 5 MEMBER KORNETSKY: I have seen so many 6 different types of people serve this role for 7 different types of studies, that if I had to sit down 8 and write what appropriate qualifications -- you know, 9 whether it's a social or behavioral study, whether 10 it's a medical intervention. The regs say that IRB 11 members. You know, just because they're an IRB 12 member, does that make them appropriately qualified? 13 It's a yes for some of our IRB members for some 14 studies, definitely not for others. 15 So, I agree with you, it's not giving a 16 lot of guidance, but I would be careful on this one on 17 giving too much guidance that may shut doors. But 18 that's my own feeling and experience. 19 MEMBER FISHER: I do think you raise one 20 interesting point about this is, if we can't figure 21 out what it is, should the bullet even be there? So, 22 you know what I mean, we could see education, training 139 1 or supervision necessary, I mean there's a lot of 2 language there. 3 MEMBER KORNETSKY: But this -- but it's 4 saying, Celia, is taking into consideration the nature 5 of the research and understanding. I mean, it is 6 giving some guidance to say that, you know, one size 7 may not fit all. And I think that might be an 8 important message. 9 MEMBER FISHER: But I think having 10 appropriate qualifications is before the fact. 11 MEMBER KORNETSKY: Okay. 12 MEMBER FISHER: And I think what we would 13 want to be promised was, if we want to keep this, that 14 there would be supervision, training, or previous 15 education. So, it's just, it's -- 16 MEMBER KORNETSKY: Okay. I think -- 17 supervision of advocate? I mean, who -- I think -- 18 MEMBER FISHER: We're training that, okay 19 -- 20 MEMBER KORNETSKY: Well, I'm not sure 21 about training. I don't know -- 22 CHAIR PRENTICE: Why don't you take it 140 1 back 2 MEMBER KORNETSKY: Yes. 3 CHAIR PRENTICE: -- and discuss it in the 4 subcommittee, -- MEMBER KORNETSKY: Yes. 5 CHAIR PRENTICE: -- because it's -- we're 6 going to table that recommendation anyways -- 7 MEMBER KORNETSKY: Yes. 8 CHAIR PRENTICE: -- and go ahead and see 9 if you can't come up with a modified recommendation. 10 MEMBER JONES: And then, just as you're 11 considering things, just where the next bullet, have 12 the appropriate time to commit to the expected ongoing 13 role, including meeting with. When I read that, then 14 I would say I would have an expectation that the 15 advocate would have met with every participant? 16 MEMBER KORNETSKY: I think that's an 17 advocate, yes. 18 MEMBER JONES: Is that actually what the 19 assumption is? 20 MEMBER KORNETSKY: I mean, I don't think 21 that that's necessarily -- 22 MEMBER JONES: So that they wouldn't 141 1 advocate for the group, but they actually would have 2 done a judgment for each one? 3 MEMBER KORNETSKY: Well, you need to 4 understand the interactions. I mean, that's what it 5 is. You need to understand. 6 MEMBER FISHER: Remember, this is in lieu 7 of parental permission. What it's saying is, what we 8 learned is, that in many instances, the legal 9 guardian, which is the state, has never seen -- 10 MEMBER KORNETSKY: Has no idea, yes. 11 MEMBER FISHER: -- these children. 12 MEMBER KORNETSKY: Has no idea. 13 MEMBER FISHER: They're a number. And so, 14 what was important was that, in order to substitute 15 for a guardian permission, understanding that for non- 16 wards, it's someone who has a personal knowledge of 17 that child, that somebody has or could obtain, 18 personal knowledge of each child to make a decision 19 about their participation. 20 MEMBER JONES: So, I guess the point then 21 is, then maybe you repeat it in your last bullet, 22 become familiar with the child's behavior and social. 142 1 I guess the one thing that sort of clues you off is 2 that you have the appropriate time to commit. You 3 know, what you really want to make sure is that they 4 have done that role and, in fact, have met with each 5 of the subjects. 6 MEMBER KORNETSKY: I think maybe we may be 7 able to combine some of the second things with the 8 last one, to have the time and be able to become 9 familiar with, to combine those two. 10 MEMBER JONES: Right. 11 MEMBER KORNETSKY: Okay. 12 CHAIR PRENTICE: Neil? 13 MEMBER POWE: I'm sorry about this. 14 You've raised a question that makes me now think about 15 the relationship of bullet two and bullet three and 16 that is, in bullet two where you talk about conflicts, 17 I am not sure that we should prohibit the research 18 study from having funding for the support of the 19 advocacy -- 20 MEMBER KORNETSKY: We don't -- we agree 21 with you. 22 MEMBER POWE: -- role. 143 1 MEMBER KORNETSKY: Absolutely. 2 MEMBER POWE: So, we're clear that someone 3 could ask, have support in the research study for the 4 advocacy role -- 5 MEMBER KORNETSKY: That's correct. 6 MEMBER POWE: -- but then there's a wall. 7 After that money passes, there's a wall that -- 8 MEMBER FISHER: Right. 9 MEMBER KORNETSKY: Absolutely. 10 MEMBER POWE: -- the advocate. I just 11 want to make absolutely sure. 12 MEMBER KORNETSKY: That's why we were 13 concerned about putting in employment and those types 14 of words because people may think that that's related. 15 MEMBER FISHER: And that's why we just 16 altered this to contractual requirements or financial 17 gains that depends upon the number or types of 18 subjects required for recruitment enrollment and 19 ongoing participation. Because that's the only thing 20 that that advocate is going to be responsible for. 21 MEMBER POWE: Right. And if this is a 22 very large study, that could be a huge -- 144 1 MEMBER KORNETSKY: Absolutely. 2 MEMBER POWE: -- financial burden to the 3 IRB, if the IRB weren't able to get money from, let's 4 say, a sponsor for -- 5 MEMBER KORNETSKY: Right. 6 MEMBER POWE: -- this activity. 7 MEMBER JONES: You know, if we are going 8 to -- if the committee is going to re-look at this, 9 too, then, you know, going back to recommendation one, 10 not just to also do a little homework on the, you 11 know, how would this apply to some of the 12 international studies would be helpful, you know, as 13 you're bringing it back for -- to actually look at 14 that. 15 MEMBER KORNETSKY: All right. So, we're 16 bringing back number two. 17 CHAIR PRENTICE: Number three. This is a 18 situation where you have to have an advocate for 406, 19 407, under the 409 requirements, but this is applying, 20 as appropriate, IRBs should consider applying the 21 requirements for appointing an advocate when the 22 classification of the research is 404 or 405. It's 145 1 not requiring them to do so, it's just simply saying 2 consider. 3 Discussion, comments, questions? 4 MEMBER JONES: You know, I guess going 5 back to, is that the consideration of an unfunded 6 mandate. If we are really raising the bar in terms of 7 what the ward or the advocate is supposed to be doing 8 for each of the different participants, that they're 9 spending time and they're, in a sense, a necessary 10 part of the research. You know, just, I guess you 11 think about -- 12 CHAIR PRENTICE: Well, you are -- 13 MEMBER JONES: -- the resources and just 14 making sure that there are ways to actually ensure 15 that this kind of research can go forward because we 16 are asking, in a sense, for a new participant to be 17 part of the research. 18 CHAIR PRENTICE: Well, I think the 19 operative word here is consider and we also have to 20 remember 111(b). If we classify a ward, even 21 participating in a 404 or 405 study, as vulnerable, 22 they need additional protections. There is no 146 1 specification under 111 as to what those additional 2 protections should be. This is one possible 3 additional protection that is not mandated. Let the 4 IRB decide. 5 MEMBER JONES: And, Ernie, you know, I do 6 agree with you but I also keep on hearing from my 7 colleagues that once things get into guidance, it can 8 quickly move into the next level of expectation. 9 CHAIR PRENTICE: And I appreciate that. 10 MEMBER FISHER: I tend to -- I think 11 Nancy's raised a very good point. 12 CHAIR PRENTICE: Yes. 13 MEMBER FISHER: I think, when we take this 14 back to the committee, we should really think about 15 that because what we put in recommendation two is very 16 expensive. And I think we need to think about both 17 recommendation two, you know, are we dictating 18 something ongoing that is more than what would be 19 required? I think we want to go back to that language 20 and not be creating, you know, a very expensive 21 administrative position, in some sense, full-time, a 22 lot of people, you know, it depends on the size. But 147 1 I do think, and in that sense taking into account the 2 international, is interesting as well. 3 But I think what we're seeing is that 4 recommendation two may place a limit on, I think what 5 you were saying, whether for 404 or 405, IRBs would 6 ever consider this because it looks so expensive in 7 number two. So, I think it's certainly something to 8 think about. 9 CHAIR PRENTICE: Let me make a suggestion. 10 Since three is clearly tied to two and since you've 11 typed two, or you've tabled two, I suggest it's not 12 productive to continue discussing number three, in 13 consideration of the time, so would that be 14 acceptable? 15 UNIDENTIFIED SPEAKER: Fine. 16 CHAIR PRENTICE: Plus, Bern has a comment 17 that he'd like to make as well. 18 SECRETARY SCHWETZ: Well, it isn't obvious 19 that this is a recommendation for OHRP, number three, 20 and some of the ones that follow or for FDA. So, my 21 question is, for whom is this a recommendation? If 22 it's a recommendation for the IRB community, things 148 1 for them to consider independent of going through 2 OHRP, then looking down the road, this isn't the 3 recommendation that would go to Secretary Leavitt. 4 You want this to reach out to the IRB community. 5 MEMBER FISHER: You're talking about 6 recommendation three, right? 7 SECRETARY SCHWETZ: Three and beyond, 8 where you're giving some thoughts to the IRB community 9 as opposed to asking OHRP to write guidance to require 10 that there be an advocate for all groups, all 11 categories. 12 MEMBER KORNETSKY: Well, I'm -- I mean 13 you're bringing up an interesting point, Bern, and I'm 14 trying to think how this is different from some of the 15 other things that we're recommending. 16 SECRETARY SCHWETZ: Susan, I see the 17 difference in that you're not asking OHRP to take a 18 position on this. This is, from your experience -- 19 MEMBER KORNETSKY: Okay. 20 SECRETARY SCHWETZ: -- you're recommending 21 that this is how IRBs should think, as opposed to us 22 endorsing it and having it be translated into another 149 1 near regulation. But now they've expanded that you 2 have to have an advocate for all categories. And I 3 don't think OHRP wants to be in a position of 4 increasing that additional regulatory burden. 5 MEMBER FISHER: Okay. I think if we go to 6 four, that may be part of regulations. I think this 7 is consistent with regulations. It's just letting 8 people know they've got to be alert, I believe, Ernie 9 and Bern, I believe, four. 10 MEMBER GYI: Susan, this would be 11 analogous to a subject participating in a non- 12 pediatric study and then becomes incarcerated -- 13 CHAIR PRENTICE: Right. 14 MEMBER KORNETSKY: Yes. 15 MEMBER GYI: -- which then has to be 16 reevaluated. 17 MEMBER KORNETSKY: Right. 18 MEMBER FISHER: Can I ask a question? 19 There may be research where you have no idea that 20 somebody became a ward. And what are the implications 21 of knowingly and whether knowingly should be put in 22 here or -- 150 1 MEMBER KORNETSKY: It doesn't say. It 2 doesn't -- I mean, that's the last point. You know, 3 the message, if some -- you need to know. I mean if 4 someone is in a research trial, I mean, you need to 5 know if they become a ward. I mean, you can't dismiss 6 them of this responsibility because the investigator 7 doesn't know. 8 MEMBER FISHER: Right. 9 MEMBER KORNETSKY: I mean, it's a real 10 practical issue and problem. It's a real, I mean, 11 it's a huge issue and problem. But I can't say, you 12 know, well, if I didn't know, then I don't have to 13 worry about it. 14 MEMBER FISHER: I agree. Obviously, 15 that's the ideal, but it could be that it doesn't come 16 to anybody's attention until the second time the child 17 came. I mean, who is to bring -- there's one thing 18 which I think is -- I don't know the answer, I'm just 19 raising the question because this -- 20 MEMBER KORNETSKY: Yes. 21 MEMBER FISHER: -- can really place all 22 IRBs in violation, if an investigator had no idea that 151 1 custodianship or -- maybe, like you said, the same 2 biological parent is bringing the child to study, but 3 has lost their legal rights. 4 So, one of the issues, I don't think we 5 can address at this meeting, but, I mean, we can't 6 decide at this meeting, but it would be good feedback 7 and also from OHRP in terms of there's one thing where 8 you can anticipate that wards of the state will likely 9 become involved in the study, but how much does this 10 involve not knowing and does it leave room for as soon 11 as it becomes apparent, are there supposed to be 12 questions that are asked every time somebody shows up. 13 So, I'm just not -- I wouldn't want to, you know, an 14 IRB or an investigator to be in violation for an 15 unknown. 16 CHAIR PRENTICE: This is an interesting 17 issue. It's somewhat analogous to the subpart C 18 discussion we had, in some respects, but in other 19 respects it's clearly not. 20 I'd be interested to know what OHRP's 21 position is on this because, quite frankly, I don't 22 know what it is. Has OHRP taken a position relative 152 1 to 409 in a federally funded study when a child who is 2 not a ward is enrolled in research and then 3 subsequently becomes a ward? Can somebody from OHRP 4 comment on that? Where is the guy in the uniform? 5 MEMBER FISHER: He's hiding but he's over 6 there. 7 (Laughter.) 8 CHAIR PRENTICE: Okay. Where is Dr. 9 Carome? 10 MEMBER KORNETSKY: He moved a couple rows 11 back from us. 12 MEMBER FISHER: Right. 13 CHAIR PRENTICE: Yes, you were in the 14 front row yesterday, what's going on here? 15 DR. CAROME: A new strategy. 16 (Laughter.) 17 DR. CAROME: We don't have formal guidance 18 statements on that topic. 19 CHAIR PRENTICE: Okay. All right. I'm 20 not going to ask for an opinion. 21 MEMBER FISHER: You know, language that 22 we've used in some other standards that I've been 153 1 involved in is, you know, if the investigator knows or 2 should have known, but I think that's the kind of 3 language that we can play with or bring back. 4 But, I guess, my question to SACHRP and to 5 OHRP is is this an issue that needs to be addressed or 6 is it not a critical issue? That if the investigator 7 does not know a child has become a ward and then 8 discovers it later, were they in violation. 9 CHAIR PRENTICE: They're not in violation 10 because OHRP doesn't have a position right now. And 11 this is not -- 12 MEMBER KORNETSKY: We don't want case law 13 on this. 14 CHAIR PRENTICE: Let me ask you this. 15 First of all, I assume that you feel that these 16 additional protections offered under 409 are necessary 17 when a child becomes a ward. I'm making that 18 assumption because that's the basis of your 19 recommendation. And you're not comfortable with 20 saying, well, okay, we don't have to apply 409 because 21 they are in the absence of OHRP guidance, there isn't 22 any, we could use 111(b) and decide what additional 154 1 protections are necessary as an IRB. And you're not 2 comfortable with that. You want something more 3 specific. 4 MEMBER KORNETSKY: No, I think it would be 5 totally inconsistent, at least with what we've seen 6 before with prisoners, that has gotten a lot of IRBs, 7 you know, having a lot of problems. 8 CHAIR PRENTICE: However, the latest 9 letter we sent to the Secretary, which has been 10 accepted by the Secretary, has a provision for 111(b) 11 being used for individuals who enroll in research as 12 unincarcerated people. You don't want to apply 13 subpart C, -- 14 MEMBER KORNETSKY: Okay. 15 CHAIR PRENTICE: -- assuming that that's 16 going to go through the entire system. So, that's the 17 genesis of my question. Is this something that you 18 feel is necessary? 19 MEMBER KORNETSKY: Well, I think we need 20 to bring that back as an alternative. I mean, I think 21 we, I mean, I think the way I personally think about 22 this is, you need something. You know, something 155 1 significant has changed in that child. You need 2 something. 3 CHAIR PRENTICE: Okay. 4 MEMBER KORNETSKY: Weather it's reverting 5 to 409 or just going back to, you know, subpart A, the 6 vulnerable children, I think is a very important 7 issue. And I don't think we really talked about that 8 as another possibility. 9 MEMBER SELWITZ: Can I ask Susan a 10 question? Because I think, I mean, that's the crux. 11 When I had read recommendation four, I thought of the 12 entire controversy that raged and I know how strongly 13 certain aspects of the community feel and you go back 14 to what we said in C. So, I think the real crux is 15 that if you had a child and you had already applied 16 subpart D, so you have already applied some additional 17 protections, all right, I mean because this seems to 18 be based, you know, the assumption appears to be here, 19 this child, that decision was already made. I mean, 20 I'm just reading how it's currently written. 21 So, I think the real question is, it's not 22 like that child has not had additional protections so 156 1 do you feel strongly, and how strongly, that in fact 2 that even though there have been additional 3 protections, even more are needed because of the 4 status change? 5 MEMBER KORNETSKY: I think it really 6 varies. But, I think, if you're talking about some 7 type of drug trial, I mean, I think there could be 8 safety issues, they're not living where they lived 9 before. People don't, you know, or may not be able to 10 bring them to the hospital for their followup care. 11 I mean, I think there could be, there probably are 12 lots of situations where just the protections for 13 children but, you know, when you get parental 14 permission, you're thinking that that parent is acting 15 in that child's best interest for that study. 16 Following that child will, you know, determine when 17 they, you know, when they can't -- when they want to 18 withdraw. I think it's open when that all changes. 19 These are kids that are put in foster homes. 20 MEMBER FISHER: I think these are -- I 21 think what we did not consider at the meeting, because 22 this was all so new to us, and I think that what Susan 157 1 put together was so well done and very insightful, but 2 we didn't think about these down sides. We were 3 thinking about protection. And I think it is valuable 4 for us to just think a little more about the practical 5 down sides of the protections that we didn't think 6 about. 7 MEMBER KORNETSKY: Very good. 8 CHAIR PRENTICE: Okay. Can I suggest that 9 because you've tabled recommendations two and three, - 10 - 11 MEMBER KORNETSKY: We table four. 12 CHAIR PRENTICE: -- and, once again, 13 you're talking about advocates here, -- 14 MEMBER KORNETSKY: Yes. 15 CHAIR PRENTICE: -- so, table number four. 16 Bring the concerns of SACHRP back to your subcommittee 17 and discuss them and then come back. 18 MEMBER JONES: And then, I don't know if 19 they would find it helpful, but if we're going to work 20 through the rest of the recommendations, we can sort 21 of use that if there are any sticking points that we 22 would like more clarification just to give you as you 158 1 consider it. 2 MEMBER FISHER: Yes, that's fine. 3 CHAIR PRENTICE: Yes. Now, we have eight 4 minutes left, nine minutes left and see if we can try 5 to get some sense of five, six, and seven. I would 6 suggest that there's no reason to try to approve any 7 of these. 8 MEMBER KORNETSKY: That's correct. 9 CHAIR PRENTICE: All right. Let's just go 10 through and try to identify the issues. All right? 11 MEMBER KORNETSKY: Yes. 12 CHAIR PRENTICE: So, number five. 13 MEMBER FISHER: I think five and four, the 14 issues are linked. 15 CHAIR PRENTICE: Yes, they're linked. 16 MEMBER FISHER: So, I think we know the 17 problem. 18 CHAIR PRENTICE: All right. So, they're 19 linked. So, why don't we skip number five and look at 20 number six. 21 I was -- I didn't quite understand that 22 second bullet point, the need to notify the IRB when 159 1 a ward is initially considered for research. 2 MEMBER KORNETSKY: I think really it's 3 just the -- they are two point, in order to enroll 4 someone and then they become, when they become a ward. 5 I mean, it's probably not worded well. 6 MEMBER SELWITZ: So, what you're saying is 7 that really that second item is that you've approved 8 a study -- 9 MEMBER KORNETSKY: Yes. 10 MEMBER SELWITZ: -- that didn't involve 11 wards and then someone becomes a ward. Is that right, 12 Susan? 13 MEMBER KORNETSKY: No, when, even if you - 14 - right. You approve the study but you need to 15 appoint a ward -- you need to appoint an advocate. A 16 ward comes along, I mean not all studies are all 17 wards, I mean there may be some, and that will be 18 dealt with up front. But you approve a study and 19 then, you know, a patient, a subject becomes available 20 who is a ward. You need to figure out if the IRB 21 needs to appoint an advocate. 22 MEMBER FISHER: I think, let me just say, 160 1 I think this is relative to Bern's comment because I 2 think whether or not this is a recommendation or a 3 background insight should be a point rather than a 4 recommendation. Because I think what, you know, 5 Susan, in her experience has also found is, is that 6 there is great legal ignorance within the IRB 7 community about this issue and that the issue needs to 8 be anticipated, not only by the IRB, but also by 9 investigators to whom it may be relevant. So far, 10 there's very little out there in terms of that kind of 11 guidance. 12 So, how we, you know, whether this is 13 phrased as a bullet point rather than a 14 recommendation, I think we can talk about, but it's 15 clearly something that -- it's very difficult to 16 follow 409 without IRBs understanding or having some 17 legal advice about when it kicks in. 18 MEMBER KORNETSKY: Really, that's the 19 thing. When a ward is eligible, the IRB needs to do 20 something so, the IRB needs to be notified. I mean, 21 it's just that. It's as simple as that. 22 CHAIR PRENTICE: Who is notifying the IRB? 161 1 MEMBER KORNETSKY: The investigator. This 2 is saying that the IRBs, in collaboration with the 3 investigators, have to have guidance and education to 4 investigators so investigators know. Investigators 5 don't know. They don't think there's anything 6 necessarily different when a ward comes in versus, you 7 know, a parent. So, they need -- there's an extra 8 requirement that an advocate be appointed for most, 9 you know, for non-beneficial research, and they need 10 to -- it's more the institutional policy. 11 CHAIR PRENTICE: Okay. So, I guess I'm 12 confused. What's -- the base of my confusion is 13 initially considered. Would it be clearer, the need 14 to notify the IRB when a ward will be a participant in 15 research? 16 MEMBER FISHER: I think what -- 17 MEMBER KORNETSKY: Will be considered for 18 a participant. 19 MEMBER FISHER: What Susan is saying is 20 somebody -- 21 MEMBER KORNETSKY: You need the advocate 22 to decide whether they're going to be or not. 162 1 MEMBER FISHER: Somebody may have brought, 2 an investigator may have brought this to the IRB under 3 a 406. 4 CHAIR PRENTICE: Okay. 5 MEMBER FISHER: They didn't tell the IRB 6 that wards would be included. I mean, the concern is 7 -- 8 MEMBER KORNETSKY: Most of the research. 9 MEMBER FISHER: -- that they did not tell 10 the IRB. 11 CHAIR PRENTICE: Okay, I see it. 12 MEMBER FISHER: So, that's what that 13 second bullet is, -- 14 CHAIR PRENTICE: Okay. 15 MEMBER FISHER: -- that they must tell the 16 IRB and there needs to be some institutional education 17 about -- 18 CHAIR PRENTICE: Okay. 19 MEMBER FISHER: -- how important this is. 20 Ernie, I think Sally has something. 21 CHAIR PRENTICE: Yes? 22 MEMBER FLANZER: Ernie, it might be useful 163 1 to think about this a little bit like an adverse 2 event. Not in a pejorative sense, but the PI has 3 certain responsibilities when things change. 4 MEMBER KORNETSKY: Right. 5 CHAIR PRENTICE: I see, okay. 6 MEMBER FLANZER: And the condition of 7 becoming a ward is that kind, to me, is that kind of 8 change. 9 CHAIR PRENTICE: That would taken care of 10 by the third bullet point, would it not? 11 MEMBER KORNETSKY: Well that's -- there 12 are two points. Most pediatric research we approve, 13 you know, 400 protocols. None of them have, 14 specifically, have we thought necessarily because, at 15 our institution -- 16 CHAIR PRENTICE: Okay. 17 MEMBER KORNETSKY: -- about wards. 18 CHAIR PRENTICE: Okay. 19 MEMBER KORNETSKY: If a ward walks into 20 the door -- 21 CHAIR PRENTICE: Right. 22 MEMBER KORNETSKY: -- and is eligible for 164 1 one of those protocols, -- 2 CHAIR PRENTICE: Right. 3 MEMBER KORNETSKY: -- the IRB needs to set 4 up an advocate. 5 CHAIR PRENTICE: Need to be -- 6 MEMBER KORNETSKY: The PI needs to notify. 7 CHAIR PRENTICE: Yes, he needs to notify 8 the IRB. 9 MEMBER KORNETSKY: And that's the weakest 10 link, right now. 11 CHAIR PRENTICE: Okay. Just, not to word 12 smith now, -- 13 MEMBER KORNETSKY: Yes. 14 CHAIR PRENTICE: but I would suggest going 15 back and making it very clear what you mean by that. 16 I understand the first and the third bullet point 17 completely. 18 MEMBER KORNETSKY: Okay. 19 CHAIR PRENTICE: I'm not confused at all. 20 I think the wording could be a little bit clearer in 21 the second one. All right? 22 MEMBER KORNETSKY: Yes. 165 1 CHAIR PRENTICE: Neil? And then Felix. 2 MEMBER POWE: Just real quick. The third 3 bullet suffers from the problem that we had in 4 recommendation four of knowing, putting the burden on 5 the investigator to know, and the issue of whether 6 every investigator is going to have to ask every, 7 periodically, about this issue, saying it comes up in 8 prisoner research as well. 9 MEMBER KORNETSKY: I'm going to go back. 10 I mean, this also has implications. I mean, I'm from 11 a medical institution for clinical care. I'm going to 12 go back and talk with legal counsel and some of our 13 investigators. Because, you know, the person who 14 signs the surgical consent if someone becomes a ward 15 it's as much of an issue that it shouldn't be, you 16 know, someone who walks in the door. And I get calls 17 all the time, you know, Johnny's here with grandma, 18 she has a piece of paper, can she consent to research. 19 But again, I'm in a facility that is a medical that is 20 very attuned to these issues but I'm going to go back 21 and do some inquiring about how that actually happens. 22 MEMBER FISHER: And I just wanted to 166 1 clarify. Mike, were you saying that OHRP doesn't have 2 a policy regarding if during the course of research 3 someone becomes a ward, that 409 may not automatically 4 be applied, necessarily? 5 DR. CAROME: No. I addressed the question 6 about the investigator having or not having knowledge 7 of that and the expectation that the investigators 8 will know. That's the issue I think Ernie asked me 9 about. 10 MEMBER FISHER: Okay. 11 CHAIR PRENTICE: No, no. 12 (Laughter.) 13 CHAIR PRENTICE: No. I asked whether or 14 not 409 applies to children who are enrolled in 15 research in a non-ward status, in the middle of the 16 project they become wards, does the IRB have to go 17 back and then apply 409? And, my understanding of 18 your response was you don't have any guidance on that. 19 DR. CAROME: We don't have any guidance 20 issued on that. I think if an individual posed that 21 question in a real case, you know, an IRB has that 22 situation, they call, we say they must apply 409 to 167 1 that research, if it's in category, again, 406 and 2 407, which are uncommonly used categories of research. 3 Because they're talking in the context of perhaps 4 apply wards for all the categories, which is not a 5 current regulatory guidant. 6 CHAIR PRENTICE: Okay. 7 DR. CAROME: So, we have someone is 8 enrolled in research approved under 407 who wasn't a 9 ward and became a ward and that was known to the 10 investigator -- 11 CHAIR PRENTICE: Okay. 12 DR. CAROME: -- we would expect 409 to be 13 implemented appropriately. 14 CHAIR PRENTICE: Okay. So, in light of 15 that clarification, bear that in mind when you -- 16 MEMBER FISHER: Definitely. 17 CHAIR PRENTICE: -- re-look at 18 recommendation number four. 19 MEMBER FISHER: Definitely. 20 CHAIR PRENTICE: Okay? Yes? 21 MEMBER JONES: Well, since I always say 22 the opposite, I would just like to say I really like 168 1 the spirit of this recommendation, you know, to enable 2 this, everybody to move in the right direction. 3 CHAIR PRENTICE: All right. It seems to 4 me that all of these issues are linked, all these 5 recommendations are linked. They're all tabled. 6 We've raised a number of issues relative to all of the 7 recommendations and that will be transmitted back to 8 the subcommittee for further consideration and a 9 report will be issued in July on this. 10 So, with your agreement, I suggest we 11 break for lunch and come back here promptly at 1:00. 12 Thanks for all your hard work. 13 (Whereupon the foregoing meeting recessed 14 for lunch at 12:02 p.m.) 15 16 17 18 19 20 21 22 169 1 A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 2 1:09 p.m. 3 CHAIR PRENTICE: May we please get started 4 again? 5 We now have the public comment period, 6 which will last until 1:30, as necessary. And we have 7 some people who have signed up, but feel free, if you 8 have not done so, to ask for time to comment. 9 I also want to indicate that, if there is 10 a desire, we can also have another public comment 11 period at 4:30. We're technically supposed to adjourn 12 at 4:30, but you all know that schedule at the end of 13 the day is somewhat flexible. So, if there is a need 14 to have another comment period, particularly on the 15 international research, after you've heard the panel 16 presentations and the discussion, we will accommodate 17 that request. 18 Now, the people that I have on my list are 19 two individuals and the first one is Cami Gearheart 20 and you know the protocol. Please state your name for 21 the record and your affiliation. And is Cami here? 22 Where are she? All right. There you are. 170 1 MS. GEARHEART: Hi. Good afternoon, Dr. 2 Prentice, and the committee. Thank you for the 3 opportunity to comment. I always enjoy coming to 4 these meetings. We enjoy being able to observe. 5 I should back up. I'm Cami Gearheart, I'm 6 with Quorum Review, an independent IRB, located in 7 Seattle, Washington. We like to keep an eye on what 8 SACHRP is doing. You air the issues of importance to 9 us that are creating difficulties and issues for our 10 Board and our organization and we appreciate the 11 solutions that have come out of the committee to date 12 and we look forward to the solutions that are 13 continuing to be developed here. 14 I wanted to say a few comments. I had an 15 opportunity to observe the workshop held last fall on 16 alternative modes of IRB review. And we really 17 appreciated the opportunity to observe the 18 proceedings. I know, in the future, there will be 19 additional meetings at which the public is invited, 20 but it was very hopeful for us, as an independent IRB, 21 to understand the pressures and concerns of 22 institutions that are looking at the centralization 171 1 process. 2 I have to say, on one hand, pleasantly 3 surprised by, in some parts, the level of acceptance 4 and encouragement for the centralization process. I 5 was taken aback in some other areas by the levels of 6 hostility in some pockets. But, I think, the notion 7 I came away with was, you know, as the academic 8 medical centers move toward centralization, 9 independent IRBs may or may not be part of the 10 solution. It seems as if the medical centers have 11 some really important issues of financial support and 12 liability to work through. And it may be that 13 collaborations within the institutions and among 14 institutions are going to help address those concerns. 15 But we certainly would welcome to continue to have a 16 place at the table. Independent IRBs have been 17 conducting multi-state site research in a centralized 18 manner for a couple of decades and we are happy to 19 share whatever lessons we have learned, both good and 20 bad, with our academic colleagues. 21 So, again, thank you for the opportunity 22 to make some comments. I look forward to the 172 1 afternoon's proceedings. 2 CHAIR PRENTICE: Thank you. Cami, as yo 3 know, we're going to have a public conference on 4 alternative IRB models and, certainly, the independent 5 IRBs will be represented at that conference which may 6 occur sometime in the fall, possibly. 7 The next individual I have on my list is 8 Linda Ehler. 9 MS. EHLER: I thank everyone for the 10 opportunity to speak as well and I hope I can 11 articulate myself as well as the previous speaker. 12 I would just like the committee members to 13 keep in mind that when you make recommendations that 14 have state laws included, that we really should be, we 15 should broaden that, those comments, to federal, state 16 and local laws, just to be cognizant that it is 17 consistent throughout any of the recommendations that 18 you put forth to the Secretary. Because one of the 19 discussions this morning we changed letter D and made 20 sure there was federal, state and local laws, but then 21 E didn't carry that forward. So, if there is 22 consistency, that would really help the international 173 1 community. 2 I also wanted to bring up a point that 3 came from this morning's slides as well. When you 4 think about the international setting, and when 5 children become wards, etcetera, physical custody may 6 be different from legal custody and this is very 7 applicable to the international setting. And that was 8 on the slide that was entitled "Practical Issues To 9 Consider Before We Think About Guidance." So, I 10 really would like to ask the committee to keep that in 11 mind, as well. That this really happen frequently in 12 our international sites. 13 Oh, I'm sorry. I'm Linda Ehler. I'm 14 speaking on behalf of myself. I'm a nurse consultant 15 in the Regulatory Affairs Branch of the Division of 16 AIDS, National Institute of Allergy and Infectious 17 Disease, National Institute of Health. 18 And a third comment I have has to do with 19 the ward comments that we had, that was discussed this 20 morning. It was recommendation number four, what to 21 do if they discover that an individual or child 22 becomes a ward during the course of research. Again, 174 1 I would like the committee to think about what happens 2 if you suspend research. There was discussion that 3 the IRB would then need to reconvene and have an 4 advocate in place and reconsider the research with an 5 advocate in place. 6 This issue comes up with prisoners, where 7 if the investigator and the IRB concurs, whether, if 8 it's in the best interest of the prisoner to continue 9 on study while this additional IRB determination is 10 being made. You may also want to consider that point 11 as well when you have wards. Again, I'm thinking in 12 the international setting. I don't want to get into 13 therapeutic misconception, but if we have, in our 14 international setting, and there are children that are 15 getting some benefit for participating in the trial 16 and they all of a sudden become a ward and the IRB 17 needs to now reconvene with an advocate in place, say 18 -- well, I'm sorry. Actually, I take it back. 406 19 and 407. 20 But, if you do go further on and request 21 an advocate be in place for all research, then that 22 would be a consideration as well. 175 1 And, lastly, the division, we've had 2 issues -- I'm part of a branch that looks at our 3 individual sites and the IRB memos that come in fro 4 our individual sites when they participate in Division 5 of AIDS Research. And what we had found in some of 6 our pediatric trials, that the IRBs are not really 7 documenting their determination of pediatric risks. 8 And we've made an effort, in the Division, to go out 9 and do training on this aspect. So, they're aware 10 that there is a need to do this in the regulations, 11 but they don't often, we don't see any evidence of 12 them documenting it. 13 So, all this discussion that we had this 14 morning on wards, actually, goes back to the need to 15 train IRBs and investigators about the needs to 16 document their pediatric risk determinations. 17 Thank you. 18 CHAIR PRENTICE: Thank you, Linda, for all 19 of those comments. As you know, the subcommittee is 20 going to go back and rethink all of the 21 recommendations with regard to 409 and bring back 22 modified recommendations at the July meeting. So, I'm 176 1 sure that all of these issues will be considered. 2 It's my understanding that there are at 3 least one other individual, perhaps more than one, who 4 has not signed up on the list but would like to 5 comment. Is that correct? 6 MR. BARTLETT: Hello. My name is Ed 7 Bartlett. I'm with OHRP. 8 I want to commend the children's 9 subcommittee in terms of the enormous research and 10 work that you've done. 11 I'd like to point out, though, what I 12 believe is an inconsistency that relates to one of the 13 recommendations that was voted on this morning. And 14 I'm looking at slide number six which quotes the 15 regulatory language about waiver of parental guardian 16 permission under 46.116(d). And it's number two. 17 It's says the waiver or alteration will not adversely 18 affect the rights and welfare of the subjects. The 19 key word there being will. 20 Then when I look at the recommendation 21 four, which is slide number 22, which is dealing with 22 the same concept here but so, we're looking at 177 1 criteria for not a reasonable requirement to protect 2 the subjects. Number one, it says the investigator 3 has provided reasonable argument the informing parents 4 may result in harm to the child. I think this is a 5 small discrepancy, but I think it's a very important 6 discrepancy because the regulatory language sets quite 7 a rigorous standard to meet. It says will. But the 8 recommendation, I think, significantly weakens that 9 requirement to may. 10 So, I wanted to bring to the attention of 11 the committee. 12 CHAIR PRENTICE: Okay. Thank you. Susan, 13 I assume you've noted that? Okay. 14 Any other public comments? All right. 15 Yes? 16 MEMBER SELWITZ: This may not be the right 17 time for me to say this but I think, since we're all 18 right on schedule, I think I will because I wanted to 19 say this. 20 This is my last afternoon on SACHRP. And 21 I just wanted to publicly thank you, as Chair of this 22 group, because you have done such an excellent job. 178 1 And I want to thank OHRP and the Director 2 of OHRP for the support in how you listen and 3 consistently listen to what we're trying to do. 4 And I want to thank my colleagues, both 5 those that are here and the ones that have already 6 departed -- departed SACHRP. 7 (Laughter.) 8 And I think what this committee has done 9 and will continue to do is of significant importance 10 for human subjects' protection. And I just had to say 11 it before I left and so we'll consider this a public 12 comment. 13 MEMBER KORNETSKY: And I second that. 14 (Laughter.) 15 CHAIR PRENTICE: Well, thanks very much 16 for the feedback. As I indicated yesterday, when the 17 ASH was here, you know, all of you are the glue that 18 keeps this committee going. You do all of the work. 19 Your subcommittee members are dedicated, committed 20 people who have done an awful lot of work. And, 21 ultimately, I think that what we do is going to make 22 a difference. I'm very enthusiastic about it and I 179 1 would hope that by the time, you know, I am ready to 2 retire or have departed that, in one way or another, 3 that all of the recommendations that you have so 4 laboriously developed, and debated, and ultimately 5 passed will be implemented for the benefit for 6 research subjects everywhere, both in the U.S. and 7 internationally and, certainly, in the IRB community, 8 you know, which is our home away from home. 9 So, I think that this enthusiasm that you 10 bring to our deliberations is infectious. And, even 11 though you're leaving SACHRP, technically, you really 12 haven't left us. As I said yesterday, you're still 13 all on subcommittees, so we expect you to continue 14 your involvement into the future. 15 So, I want to, as long as we're publicly 16 thanking everybody, and we've got some time to kill 17 anyways because our panel is out there somewhere, I 18 want to thank the involvement of the three of you who 19 are leaving SACHRP, not to mention all the rest of the 20 people who have been on SACHRP whose terms are not yet 21 up. And our new member here, who has made a 22 significant contribution already in his first meeting, 180 1 and we expect more of the same in the future. 2 So, everybody deserves a round of 3 applause, as well as the OHRP folk. 4 (Applause.) 5 CHAIR PRENTICE: Now, what we're going to 6 do in the months that remain between now and July, we 7 are going to arrange for subcommittee meetings to 8 occur here in Washington for the Subpart A 9 Subcommittee and the Children's Research Subcommittee. 10 Those subcommittees will consider all of the 11 recommendations and issues identified during the last 12 two days and they will bring back modified 13 recommendations for consideration at the next meeting 14 in July. 15 Also, between now and then, OHRP will be 16 in the process of looking at how they plan on 17 implementing the latest recommendations sent to the 18 Secretary which have been accepted, as Bern indicated 19 yesterday. So, I'm sure that by July we'll have some 20 sort of indication from OHRP in terms of their 21 progress on implementing those recommendations. 22 By July, we'll have an idea of what's 181 1 happening with the alternative IRB model initiative, 2 i.e., the next step, which is going to a national 3 conference which OHRP, and NIH, and, I'm sure, FDA, 4 and perhaps even with input of AAMC and ASCO, we'll 5 figure out how we should pursue that. So, we'll be 6 able to give you some information on that at the next 7 meeting. 8 Perhaps we'll have some sort of resolution 9 fo the adverse event problem. If not, certainly we're 10 going to get a progress report at the next meeting 11 because that's always been high on our list of 12 priorities. 13 We probably will be able to give you a 14 status report on the IO initiative, which, as I 15 indicated yesterday, Dick and David are meeting today 16 somewhere in Washington to talk about the best 17 approach for that, so we'll know more about that next 18 time around. 19 SECRETARY SCHWETZ: May I? 20 CHAIR PRENTICE: Go ahead. You've got the 21 next four minutes. 22 SECRETARY SCHWETZ: Four? The next four 182 1 minutes? 2 (Laughter.) 3 SECRETARY SCHWETZ: That's assuming that 4 the other group comes back in. 5 CHAIR PRENTICE: Okay. 6 SECRETARY SCHWETZ: Ernie, let me just 7 comment on your comment on the IRB workshop. The VA 8 was also very helpful in the workshop -- 9 CHAIR PRENTICE: Right. I -- 10 SECRETARY SCHWETZ: -- and in the 11 planning. And -- 12 CHAIR PRENTICE: Yes. I neglected VA. 13 I'm sorry, Glenn. 14 (Laughter.) 15 SECRETARY SCHWETZ: -- one thing that we 16 have discussed, we didn't know for sure how SACHRP was 17 going to turn about out on this, but we anticipated it 18 might be a national conference, so we have already met 19 several times to begin the process of discussing what 20 this could look like and when and where and all of the 21 usual things. And we have probably spent most of the 22 time trying to figure out who is the right audience to 183 1 bring to this. 2 And, based on your comments yesterday and 3 the comments that we had at the workshop, I think it's 4 possible that we would have a national conference open 5 to everybody that is targeted to specific groups by 6 virtue of the kinds of workshops or the types of 7 breakout groups that we would have. So, we may want 8 to have a breakout group for signatory officials and 9 other institutional officials. And breakout sessions 10 that are more investigator oriented, and then some 11 that are IRB oriented, or institutional attorneys, 12 however we want to mix this crowd together to talk to 13 all of these components of the enterprise that need to 14 be involved if we're going to make some additional 15 progress. 16 So that the discussion about who should be 17 sponsors and who should be on the planning committee 18 became even more critical because the array of 19 sponsors gives us leads into those parts of the 20 enterprise that we want to attract to the meeting. 21 So, we will pick up on that discussion and we will 22 make sure that we have representation on the planning 184 1 committee that is wide enough so that we can plan the 2 breadth of meeting that we think will help to move 3 this forward. 4 In the spirit of thanking people, let me 5 also thank you, Susan, and Ada Sue, and Felix for 6 having accomplished a lot for all of us, through your 7 contributions. And I have certainly learned from each 8 one of you as we have gone through these last few 9 years where you have not only told us what the 10 important issues are but you helped us to bring some 11 of them to closure to move forward on them and to 12 identify some that the other members of SACHRP staying 13 will still need to deal with. But we are very 14 fortunate to have you continuing to work on 15 subcommittees. 16 I'm not sure how we -- if we had planned 17 that intentionally, I would take credit for a good 18 plan. But it certainly is to our benefit that you are 19 willing to stay on. So, I thank all of you. 20 CHAIR PRENTICE: Okay. We are now going 21 to move into the afternoon session on the Status of 22 Research Ethics/Training Internationally. And, as I 185 1 indicated this morning, we've assembled a panel of 2 experts, but we have a couple of things to do first. 3 I would like to ask Bern to read the 4 charge to the SACHRP panel, of which all the panelists 5 are familiar, so that all of you who are in the 6 audience are aware of the kind of direction that we're 7 trying to go on this particular panel. So, Bern, 8 would you do that? 9 SECRETARY SCHWETZ: Sure, Ernie. I'm not 10 going to read the charge, I'm going to comment from 11 it. Just some thoughts that I've extracted from the 12 charge we wrote down so that the participants in this 13 panel were all working from kind of the same outline. 14 As I mentioned yesterday, we had two 15 panels on international research earlier during the 16 meetings of SACHRP, and these topics are kind of a 17 combination of illuminating and depressing. 18 Illuminating because the issue is so important. 19 Depressing because it's so large and complex. And we 20 decided, in this third panel, and I doubt that this 21 will be the last panel on international research for 22 SACHRP, but in this particular one, we wanted to 186 1 select a topic that was narrow enough that we could 2 bring in a handful of people to talk about it from 3 their own experience and give us a handle on just this 4 narrow slice of this larger international research 5 issue. 6 So, the slice that we've picked as a place 7 to begin on this more narrow cut of all of this large 8 issue was training in the area of ethics. Ethics 9 being the investigator, and ethics of being perhaps 10 the institution that is supporting the research, 11 ethics involved in the IRB, the review process, the 12 Ethics Review Board. And we wanted to look at this 13 narrow cut with the expectation that if we can have 14 some conclusions drawn from the topic of training in 15 the area of ethics of research outside the U.S. when 16 it's funded from institutions from inside the U.S., 17 that that would serve as a background for subsequent 18 discussions on other topics related in a specific 19 sense, also, to international research. 20 So, the first thing we did was agree that 21 if we're going to make this work, we should have Bob 22 Levine as the moderator because Bob has one of those 187 1 ranges of experience that allow these things to happen 2 in an illuminating way, because of his own experience, 3 but his ability to draw good information out of groups 4 of other people in his discussions. He also keeps 5 people on time and keeps them in place, so we're 6 expecting Bob to be able to execute this panel 7 discussion with significant ease this afternoon. 8 So, in the discussions with Bob, and 9 Ernie, and the rest of us, we decided the mix of 10 people for this should include regulators but, more 11 importantly perhaps, because the U.S. regulators speak 12 frequently, but it's more important that we hear those 13 voices in the context of the medical product industry 14 and agencies that fund this research that goes on 15 outside the country and those people who are already 16 involved in training programs that have to do with 17 research in the international setting, whether it's 18 ethics training or some other types of training where 19 the goal is similar to what we're trying to talk about 20 here, the training in ethics. 21 So, as we brought representatives together 22 of this nature, we wanted to be able to talk about 188 1 whose responsibility is it to do the training for 2 ethics of research conducted in developing countries. 3 Who is responsible for that? Because we're all 4 involved in it in one way or another, but who has the 5 lead responsibility for that ethics training? What 6 type of training is already available and what type of 7 training do we need that isn't out there today? And 8 also, tapping into some of those that have already 9 been involved in the training programs, what are some 10 innovative models that we could use to scale up the 11 training of ethics in the international setting? And, 12 part of what's important there is to learn, perhaps, 13 what's been tried and didn't work but also, what is 14 working, so that we can become more innovative as we 15 look toward this large task in the future. 16 There's more than enough work here to go 17 around for everybody, but we've been worried that 18 there are cracks between what individual people or 19 groups are doing, so that there may be pieces missing, 20 or they were probably redundant and, as a result, 21 we're concentrating on some things in a redundant 22 manner and other pieces of the training are not 189 1 happening at all, either in certain locations, or in 2 certain groups. 3 So, we're hoping that that would be the 4 range of discussion this afternoon. And, Bob, with 5 that -- Bob has laryngitis, so he's sparing his voice 6 but I'll stop talking for him right now and let him 7 introduce the rest of his people. 8 CHAIR PRENTICE: I'll introduce him first. 9 SECRETARY SCHWETZ: Oh, okay. Ernie. 10 CHAIR PRENTICE: What I will do is I will 11 introduce Dr. Levine and he, in turn, will introduce 12 the panelists as they are asked to present and he'll 13 take care of the moderation and all of the other 14 procedures that are necessary to keep the panel on 15 course. 16 You know, what can I say about Bob? 17 He's known to, I think, everybody in here. He's been 18 a mentor for many of us in this room. But I will 19 recite just a few of his accomplishments. He's a 20 professor of medicine and lecturer in pharmacology at 21 Yale University School of Medicine, Director of the 22 Law Policy and Ethics Corp of the Yale University 190 1 Center for Interdisciplinary Research on AIDS and Co- 2 Director of Yale University's Interdisciplinary 3 Bioethics Center. 4 Skipping down his bio, I noted that he's 5 been chair of, was chair of their IRB for 31 years. 6 I suspect that that's a longer tenure than anybody 7 else in this room has had a chair of an IRB, certainly 8 it's a lot longer than my own. He is the founding 9 editor of IRB, A Human Subjects Research, which many 10 of us subscribe to and distribute to our IRB members. 11 I consider it to be an absolutely crucial source of 12 information on research ethics for IRB members, as 13 well as investigators. And he's chair of the 14 Editorial Board. He's the author of numerous 15 publications and he is currently preparing the third 16 edition of his book, Ethics and Regulation of Clinical 17 Research, which, personally, was the first book on 18 research ethics I found in our library and checked it 19 out and read it and then I consulted it ever since. 20 So, I am really looking forward to the next edition. 21 Finally, Bob's been awarded the 22 outstanding achievement medal from the Office for 191 1 Human Research Protection in 2004 for his role in the 2 development of the Belmont Report. The lifetime award 3 for excellence in human research protection from the 4 Health Improvement Institute in 2004 and the lifetime 5 achievement award for excellence in research ethics 6 from PRIM&R, which was awarded at the last PRIM&R 7 meeting in 2005. 8 So, clearly, we're honored to have Bob 9 here with us today to guide this particular panel and 10 to give us a very brief presentation in advance of 11 serving as a moderator. So, Bob, thank you for 12 agreeing to come. 13 DR. LEVINE: Thank you very much, Ernie, 14 for that generous, very generous introduction. I 15 consider it a privilege to be here with you and I am 16 honored that you would call upon me to serve in this 17 capacity. 18 International research ethics is something 19 that I have been interested in since I got involved in 20 the CIOMS guideline writing process in the mid-1970s. 21 It's been very close to the center of my attention for 22 the last decade or so. So, that will underscore how 192 1 important I find international research ethics. 2 I'm going to give you a brief overview of 3 what goes on in international research ethics that is 4 somewhat different from what goes on in domestic 5 research ethics. I'm going to assume that everyone 6 here is throughly familiar with our regulations and 7 our ethical standards. So, I'm not going to give a 8 comprehensive overview. I'm just going to touch on 9 those aspects of research ethics that are brought to 10 the fore when people from wealthy industrialized 11 countries either sponsor or conduct research in 12 countries that we now call low resource countries and 13 used to call technologically developing countries. 14 The scope of my talk is on this slide. 15 I'm going to mention something about the attitude 16 that's reflected in the international research ethics. 17 Attitude that either is or ought to be. I'm going to 18 talk about the distinction between procedural and 19 substantive rules because this is important in 20 understanding international standards. The specific 21 guidelines I'll talk about are those that are taken 22 from the most recent iteration of the CIOMS document. 193 1 Who knows what -- does anyone here not 2 know what CIOMS is? 3 (No response.) 4 DR. LEVINE: You all do? 5 (No response.) 6 DR. LEVINE: Splendid. 7 The year 2002 is the last iteration of 8 this document. 9 I'm then going to get into the substantive 10 requirements of some of the guidelines in CIOMS 11 beginning with the most highly controversial topic of 12 choice of comparators in clinical trials, a brief 13 comment on informed consent, and then I'll talk about 14 research in communities with limited resources, a 15 brief comment on equitable distribution of burdens and 16 benefits, a comment on women as research subjects, and 17 then close with some comments on capacity building and 18 the provision of healthcare services when wealthy 19 industrialized countries sponsors and investigators 20 conduct research in low resource countries. 21 First, about the attitude. The very worst 22 thing we can do is to go out there and say we're from 194 1 America and we're going to tell you how you ought to 2 behave. That was difficult 20 years ago and it's more 3 difficult now. It's important to point out that the 4 CIOMS guidelines, themselves, are designed to guide 5 sponsors and investigators from the wealthy countries 6 as they carry out their research in developing 7 countries. It's also very important to show that we 8 are very eager to learn from them what works in their 9 cultural context and then to recognize some 10 compromises that have to be made from time to time. 11 A bit about ethical norms or rules. 12 Forgive me for those of you who already know this, 13 this is probably the majority of you, but substantive 14 rules are rules that specify what one should do. And 15 the reason that one should do it is that it's morally 16 right to do so. Or they may be negative rules. Don't 17 do that because it's morally wrong to do so. 18 Procedural rules specify what procedures 19 one should follow to accomplish the morally right 20 action. And there are two species of these. One is 21 a procedure to follow to determine what to do when the 22 substantive rules don't give clear guidance. The most 195 1 important procedural rule or procedure would be 2 consulting an institutional review board. And what 3 they do is interpret how do you apply the sometimes 4 vague substantive rules to the particular situation 5 you're dealing with. 6 A second type of procedural rule is that 7 it provides support or assistance as one attempts to 8 comply with the requirements of a substantive norm. 9 So, for example, a consent form is a procedure that 10 guides us in conducting our conversations with 11 research or prospective research subjects so that we 12 don't leave anything important out. If you look the 13 ultimate meaning of a consent form, it is not designed 14 to uphold the rights and welfare of the subject. 15 That's what informed consent is for. 16 Does that mean I'm saying something sharp? 17 (Laughter.) 18 DR. LEVINE: The reason that we have a 19 consent form, originally, is to protect the 20 institution from the subject. So, in case they come 21 back a couple of years later and say you did not get 22 informed consent from me, you left out the fact that 196 1 I was free to refuse, you can say, not only did I tell 2 you that, but I've got a signed receipt for the 3 information. 4 How we doing? Not too good? 5 The next slide would have gotten into the 6 -- 7 (Laughter.) 8 DR. LEVINE: -- very -- everyone has a 9 copy of my next slide? 10 (Chorus of yes.) 11 DR. LEVINE: And so do I. I'm now getting 12 into the CIOMS guidelines. And, by far, the most 13 controversial and most hotly contested guideline, was 14 guideline number 11, which says what is the -- what 15 are we -- what are the limits to choice of comparators 16 in randomized clinical trials? I thought we were on 17 a roll there for a minute. 18 Many of you, I'm sure, are familiar with 19 what the controversy was. The Declaration of Helsinki 20 said that you had to use the best proven therapeutic 21 preventive or diagnostic method. The drafts of the 22 CIOMS documents said, the best current intervention. 197 1 What the final CIOMS document says is that the default 2 position is that you have to provide an established 3 effective intervention. This is a term that was 4 coined by NBAC. 5 You want my to pick up my feet? Degree of 6 difficulty is 2.7. 7 (Laughter.) 8 DR. LEVINE: And the established effective 9 intervention has a very different meaning. This is an 10 intervention that clinicians in the field will say is 11 established and effective, not necessarily the best. 12 Usually, we don't know what the best is because there 13 are multiple treatments out there and we have never 14 formally compared them head-to-head in a clinical 15 trial. 16 I think we're doing good here. As well as 17 well. 18 Now, the central issue is under what 19 circumstances may one use a placebo? First you may 20 use it when there is no proven intervention, 21 obviously. 22 Secondly, when withholding established 198 1 effective intervention would result in only temporary 2 discomfort and no serious harm. This would be like a 3 placebo controlled trial for a new antihistamine to 4 treat runny noses or a new analgesic to treat 5 headaches. This, believe it or not, was highly 6 controverted and it ended up that CIOMS decided that 7 you may use a placebo in this situation. 8 Thirdly, when the use of the established 9 effective intervention, as a comparator, would not 10 yield scientifically reliable results. Sometimes the 11 withholding of standard therapy will result in 12 something more than more than temporary discomfort, 13 possibly. For example, the most controversial area in 14 the United States is placebo controlled trials of new 15 treatments for psychosis. In these circumstances it 16 seems agreed, certainly by the FDA, that in some cases 17 it's necessary to have a placebo control because an 18 active control would not give scientifically reliable 19 results. 20 And then, finally, the issue that started 21 the international controversy, is studies designed to 22 develop an effective alternative to an established 199 1 intervention when that intervention is not available 2 locally, usually for economic or logistical reasons. 3 The justification of doing this includes the 4 following. The development of this product must be 5 responsive to the health needs of the host country in 6 which you are carrying out the research. There has to 7 be a health need there. The established effective 8 intervention, as a comparator, would not yield 9 scientifically reliable results. And, at the end of 10 all of this, the product, if it turns out to be 11 effective and safe, must be made reasonably available 12 and its availability must be sustainable without the 13 continuing support that goes with the running of a 14 research program. 15 Is this a double standard? Many people 16 said it was a double standard. I think not. The 17 single standard is that the results of the research 18 should be responsive to the health needs and 19 priorities of the community of subjects and the 20 products developed must be made reasonably available. 21 Some people say this is a violation of the 22 fiduciary standard. I agree. The fiduciary standard 200 1 requires that physicians, in the course of their 2 medical practices, must have no interest that assumes 3 an equal or higher priority than the well-being of the 4 patient. When physicians are carrying out research, 5 sometimes they violate the fiduciary standard. We do 6 this routinely in the studies of pathogenesis of 7 disease and the studies of pathophysiology of disease 8 and when physicians carry out epidemiologic research, 9 they are doing things, in general, that have no 10 bearing on the well-being of the individual patients. 11 So, what I'm saying is, yes, I acknowledge this is a 12 violation of the fiduciary. But, as you can see, the 13 guidelines put strict limits on the degree of 14 violation that's tolerated. 15 Moving into guideline number three, for 16 ethical review of externally sponsored research, the 17 central point is that the ethical standards must be no 18 less stringent than they would be if the research were 19 carried out in the country of the sponsor. That 20 doesn't mean the standards have to be identical, that 21 means they have to be stringent. And stringency is 22 interpreted in the context of the culture in which the 201 1 research is to be carried out. 2 The health authorities of the host 3 country, as well as a national or a local ERC, ethical 4 review committee, it's funny that in 2002 we thought 5 we were being politically correct using this, but 6 since that time, the entire world seems to have 7 switched to the IRB, so here we are, it's time to 8 revise CIOMS again. Now, they should ensure that the 9 proposed research is responsive to the health needs 10 and priorities. 11 It's important to note that the CIOMS 12 document allows a division of labor. It doesn't want 13 to give my next slide. Well, the division of labor, 14 I don't know what happened to it, would be this, that 15 the ethical review committee or IRB in the host 16 country would be responsible for seeing to it that 17 certain universal standards are applied. For example, 18 scientific design. If the scientific design is not 19 excellent, it doesn't matter where you are doing the 20 research, it's not ethical to do it. Competency of 21 the investigators. Seeing to it that there is due 22 respect for the fundamental ethical principles. 202 1 What's left for the host country to do? 2 the host country, its IRB should see to it that the 3 principles are interpreted in ways that are compatible 4 in ways that are compatible with cultural standards. 5 For example, it's only IRBs in the host country that 6 can tell you if a trusted intermediary in the informed 7 consent process is really to be trusted. These are 8 the only people who can tell you what counts as 9 private information in the host country. There is 10 some startling differences in what's considered 11 private around the world. They will also tell you 12 what constitutes undue inducement in the light of 13 local traditions, gift exchange traditions. I walk 14 and fantasize that if we took an American IRB and 15 picked it up and put it down in Tokyo that they'd 16 never finish with the first protocol. They would find 17 so many things that looked to them like conflicts of 18 interest, they wouldn't know where to turn. This is 19 why we need this review, the details and 20 interpretations carried out in the host country. 21 With regard to informed consent, the CIOMS 22 document is uncompromising. It says that each 203 1 individual subject must be presented with all the 2 relevant facts, in this country, we would say material 3 facts, even though sometimes they don't have totally 4 unencumbered authority to act in the light of these 5 fact. As many of you know, there are some tribal 6 villages where if the governing body of the village 7 decides they are going to participate in a research 8 protocol, it's almost literally unthinkable that any 9 individual will say, but not me. I've been told by 10 people in these countries that the closest 11 approximation in Western experience to what would 12 happen to such an individual is what we call 13 excommunication. 14 The guideline also, guideline four also 15 says, that as a general rule, the subject should sign 16 a consent form. But it's essential to be sensitive to 17 what the meaning is of signing a document, even in the 18 United States, so that the circumstances under which 19 waivers and alterations might be considered should be 20 interpreted in the light of the local cultural 21 context. 22 In research in populations in communities 204 1 with limited resources, the sponsor and investigator 2 must make every effort to ensure that the research is 3 responsive to the health needs and the priorities. 4 It's not good enough to say we think you need this. 5 They must say, yes, and that's one of our priorities. 6 Any intervention or product developed will 7 be made reasonably available for the benefit of the 8 population or community. Reasonably available takes 9 into account the fact that sometimes, even at the end 10 of the trial, the country's drug registration agency 11 might say you don't have sufficient data to distribute 12 this drug in our country. There's many other 13 complications. I'm hoping we'll hear from David Lepay 14 of FDA and Jean Louis Saillot from Schering-Plough 15 about some of these complications. 16 Guideline 12 calls for equitable 17 distributions of burdens and benefits in the selection 18 of groups of subjects. Our regulations say in the 19 selection of subjects but the guidelines say groups. 20 There is concern in the last sentence here that 21 exclusion of groups or communities that might benefit 22 from study participation must be justified. 205 1 Women as research participants. The 2 potential for becoming pregnant should not, in itself, 3 be used as a reason for limiting participation. 4 However, a thorough discussion of risks to the 5 pregnant woman and to her fetus is a prerequisite for 6 a rational decision to enroll. If participation in 7 the research might be hazardous to a fetus or a woman 8 if she becomes pregnant, the sponsors should guarantee 9 a pregnancy test and access to effective contraceptive 10 methods. Where such access is not possible, for legal 11 or religious reasons, the investigator should not 12 recruit any women who might become pregnant. 13 I think you can see there is some subtle 14 compromises in here with the standards that are 15 articulated in various forms of American policy. 16 Guideline 20 is a very important, or 17 beings an important series of slides. Recognizing 18 that many countries lack the capacity for scientific 19 or ethical review, in externally sponsored 20 collaborative research, sponsors and investigators 21 have an ethical obligation to ensure that biomedical 22 research projects, for which they are responsible in 206 1 such countries, contribute effectively to the national 2 or local capacity to design and conduct their own 3 biomedical research in the future and to provide 4 scientific and ethical review. 5 That can be interpreted to mean you must 6 help them build the capacity to review the science and 7 to conduct the IRB-type of activities. 8 Capacity may include, but is not limited 9 to establishing and strengthening the independent 10 ethical review processes and committees, strengthening 11 research capacity, developing technologies appropriate 12 to healthcare and biomedical research, and training of 13 research and healthcare staff, and educating the 14 community. 15 Sponsors are ethically obliged to ensure 16 the availability of healthcare services that are 17 essential to the safe conduct of the research, 18 treatment for subjects who suffer injury as a 19 consequence of research interventions. This is a 20 distinct departure from the American regulations, 21 which don't say you had to provide treatment, you must 22 simply say whether or not it's available. In the 207 1 international context, in this specific subset of the 2 international context, we think not only is treatment 3 mandatory, but also compensation for research induced 4 injury. 5 And then services that are a necessary 6 part of the commitment of a sponsor to make the 7 product developed as a result of the research 8 reasonably available standard. 9 A final comment, this is not from CIOMS, 10 this is from me, on the topic of global injustice. 11 The distribution of wealth among the nations of the 12 world is clearly inequitable. Research did not cause 13 this and research cannot fix this. There is a 14 temptation to use international research documents as 15 devices to correct inequities. To some extent, this 16 is a reasonable and constructive activity. However, 17 we must avoid the development of guidelines that would 18 impede the efforts of sponsors and investigators in 19 industrialized countries to assist countries with 20 lesser resources in their efforts to develop treatment 21 and preventions that they can afford. 22 Thank you very much for your attention. 208 1 (Applause.) 2 DR. LEVINE: Our -- I have now, what I 3 would like to do is to ask the members of the panel to 4 come up here and join me. And I'm going to ask them 5 to sit with us until they have given their 6 presentation and then, if they find that they're not 7 able to see these screens, they could move to a better 8 seat. 9 You've got me down there? 10 UNIDENTIFIED SPEAKER: I've got you right 11 in the middle. 12 DR. LEVINE: In the middle? David, we can 13 either trade seats or trade rows there. 14 As we go along, after each speaker 15 finishes his or her presentation, I will welcome a 16 question or two only directed at clarification of the 17 speaker's comments. But I would prefer that we 18 postpone substantive comments and questions until 19 we've heard from all of them. Some of our people, our 20 panelists, are not going to give formal presentations, 21 but they will participate in the discussion when it's 22 open to all of us. 209 1 So, in that spirit, I would like to ask 2 you, if you want to ask me to clarify a point or two 3 that I made? 4 (No response.) 5 DR. LEVINE: It's extraordinary that I can 6 talk for 25 minutes and not create at least some 7 confusion. 8 (Laughter.) 9 DR. LEVINE: I'll take that as a -- 10 Now, our first speaker is a woman who 11 certainly needs no introduction in this room, Melody 12 Lin. Dr. Lin is Deputy Director of the Office for 13 Human Research Protections and responsible for the 14 management of OHRP policy personnel and budgetary 15 matters regarding biomedical and behavioral research 16 at both the national and international level. Melody? 17 DR. LIN: Thank you. Thank you, Dr. 18 Levine. 19 I have less than 15 minutes to address the 20 ten questions that Dr. Schwetz raised for this panel. 21 And I thought that I would give you, just refresh your 22 memory of that last SACHRP recommendation for 210 1 international activity from the first panel and then 2 attempt to address those ten questions. I may not 3 have all the answers but, hopefully, to serve as the 4 background for panel discussion later on. Then, I 5 will end up with the OHRP's concept for the public and 6 private partnership for research ethics capacity 7 building in the host country. 8 So, these are the three recommendations 9 from the first panel. Because of the time constraint 10 and the delayed response to the charges, I would only 11 focus on the last bullet, and that is, the federal 12 foundation partnership to build capacity in host 13 country that was recommended from the first panel. 14 So, there are ten questions that raised. 15 And I would go one by one. And you're not going to 16 expect that I have all the answers but hopefully, we 17 will reserve our discussion later. 18 First question. Are regulators in the 19 U.S. satisfied with current levels in the nature of 20 training of research ethics? In some cases, yes. 21 But, generally, not data is available. OHRP has the 22 international capacity to conduct programs since late 211 1 2002 and FDA conduct GCP inspection. Is the medical 2 product industry comfortable with the training of 3 research ethics? These are questions for industry and 4 FDA. 5 Suppose, if the answer is no, then we ask, 6 why is so much research done internationally and what 7 is done to compensate the lack of research ethics 8 training? Are funding agencies satisfied that grantee 9 and contractors are adequately trained in research 10 ethics? This is a question for wonder, NIH, CDC, 11 USAID, and so on. 12 If the answer is no, we ask why is so much 13 research done internationally and what do they do to 14 compensate the research ethics training? 15 We know that NIAID does some ethics 16 training through family health international and they 17 do some of their own. Fogarty does high concept 18 bioethics training and one would ask how much of those 19 teaching and capacity building deal with regulatory 20 compliance? How to know what's out there for the 21 research ethics training? Perhaps we can pass the 22 human subject research subcommittee international 212 1 workgroup to pool sources to get an inventory of what 2 the teaching material are there. Or, maybe, the 3 working group, international working group, can 4 identify other approaches for capacity building. 5 How to meet specific needs. To identify 6 the standardized curriculum and the ethics concept, 7 how the ethical concept can be illustrated for the 8 implementation of acceptable locally specific 9 scenarios. 10 How to get some uniform level worldwide? 11 To establish a public and private organization to 12 partnership to make the standardized curriculum and 13 the locally customized content for all nations and all 14 regions worldwide. 15 How to make the effect doable? To use the 16 distance learning technique and provide training on 17 video and it could be offered frequently and 18 repeatedly. Any group or any individual can take the 19 training at their convenience. And once the video is 20 created, there is small -- it require very small 21 resources to maintain. And the video can be made 22 available on web and other media. 213 1 Whose responsibility is it to assure 2 adequate training? Although U.S. regulation does not 3 require expressly to conduct research ethics training, 4 perhaps one can rely on those paying for research to 5 make it a condition for funding that they need to have 6 a research ethics training. And while building the 7 capacity, the research can go on. This way, 8 eventually, the ethics capacity would be built and 9 then the sponsor of the research, the funder, would 10 not have to compensate for the lack of research ethics 11 training eventually. 12 Would more rigorous training of ethics 13 decrease the risk to subjects? Anyone answer yes, 14 what is the evidence? Well, I think the call for the 15 disaster that happened in the University of Rochester, 16 the 19-year-old college student, Nicole Kwon, that die 17 of the bronchoscopy experiment, and the Jesse 18 Gelsinger's death in the gene transport research in U. 19 Penn., and the Aaron Ross death in Johns Hopkins 20 University through the asthma study, call for more 21 training and more communication. Anyone answer no, 22 then perhaps we should not worry about capacity 214 1 building or spend money on the capacity building. 2 How do we accomplish the training so that 3 subjects of research are protected? Think the access 4 to the training should be widely available, and most 5 likely the resource will come from research sponsor, 6 and the training materials should be widely accepted 7 for use worldwide and also endorsed by international 8 organization. The training should be continuous to 9 train the new people and to refresh those have already 10 been trained to bring them update. And the research 11 committee should not have why worry disparity. And 12 the training is not just a one-time training, it 13 should be open access to researcher, ethics committee 14 members and staff. And research ethics training 15 should be considered as integral part of research, not 16 an option at all. 17 Whether we can establish the public- 18 private partnership, we could also explore additional 19 measures, such as a sister institution arrangement. 20 Like, for instance, University of Washington with 21 Peru, and they have a year each ethic training, in the 22 case Western with Uganda, that Patty Marshall's 215 1 organization does. 2 And intensity and frequency of review is 3 also important. Those are research ethics committee 4 review low volume of research may lose expertise due 5 to lack of practice. Perhaps the regional review and 6 the national review would be a good interim step until 7 the research volume is built up. 8 In conclusion, I think what we need is a 9 system, for research ethics training, is a system that 10 grows. We go for research ethics training and 11 capacity building and research sponsors contribute 12 support for the training activity and it would be open 13 access to ethics committee members, staff, and the 14 researcher and it would be widely available and 15 accessible for use and to ensure the sustained use. 16 Thank you very much. 17 (Applause.) 18 DR. LEVINE: Thank you, Melody. Are there 19 are any comments? 20 (No response.) 21 DR. LEVINE: Requests for clarification? 22 (No response.) 216 1 DR. LEVINE: I've been serving on panels 2 with Melody for 25 years or more. I still haven't 3 been able to convince her to call me Bob, like 4 everyone else does. 5 Our next -- oh, I see a hand. 6 MEMBER FLANZER: I do have a question for 7 Melody. You talked about high concept bioethics 8 training. Could you explain that a little more fully? 9 DR. LIN: I think that Barbara Sina might 10 be able to explain better than I do. I think that 11 they call it a bioethics training. It encompasses 12 wider than research ethics. And I don't know how much 13 of those grantee from Fogarty are concentrating on the 14 research ethics. 15 DR. LEVINE: Thank you. Moving along now, 16 I am horrified to see that the name signs seem to have 17 been distributed by a random process. Try to sort 18 them out. Actually, the signs were distributed quite 19 properly. It's the panelists who distributed 20 themselves by random assignment. 21 Our next speaker will be David Lepay. 22 David is senior advisor for clinical science and 217 1 Director of Good Clinical Practice Programs within 2 FDA's Office of the Commissioner and its Office for 3 Science and Health Coordination. David? 4 MEMBER LEPAY: Thank you very much. 5 Well, my title here sounds very global. 6 As I have discussed this particular panel with Bern, 7 clearly the focus here is on education, education and 8 training. And, hopefully, I'll provide some segway 9 for those speakers that will follow me that are 10 involved, themselves, in programs of development or 11 oversight for product-based clinical research. And, 12 of course, that's what we're talking about when we 13 speak about FDA. 14 I want to spend just a few minutes, even 15 though I have quite a few slides on FDA basics. It's 16 important to cover these issues, because they do bear 17 quite significantly on the topic of education and 18 training, what the limitations, what the qualifiers 19 are here, based on regulations and otherwise. 20 I'll briefly go through regulatory 21 expectations for investigator training and the ethical 22 conduct of research because, again, these are 218 1 undergoing change within FDA's regulatory scheme. We 2 are in the process of making some changes in those 3 regulations. 4 I'll talk very briefly on international 5 inspection experience. But I'll also spend a little 6 more time on what I just included as my last slide, 7 the approaches that we are taking and the way we are 8 directing our own efforts, again, to develop and 9 promote education, in the ways that we have regulatory 10 authority. 11 As far as basics go, I think it's, again, 12 this is fairly obvious, but it's something that always 13 needs to be reminded, when we're talking about FDA as 14 a regulatory agency, we are talking about an agency 15 that is, essentially, purely regulatory. We are not 16 funders of research, so, therefore, we don't have the 17 leverage to require or to make changes in the way that 18 research is conducted, based on the fact that we 19 control the funding and the money that goes into that 20 research. And this is different, of course, for most 21 common rule signatories. 22 Now, it's not absolute and, in the United 219 1 States, we do, in fact, serve as sponsors. We do fund 2 some research in the area of orphan products, in some 3 studies in the areas of women's health, and some 4 epidemiologic surveillance studies, but these are 5 largely domestic. 6 Where we are sponsors of studies in the 7 U.S., we have made changes over the past two to three 8 years, recognizing, again, the need for continued 9 education in these areas. We've taken and put in 10 place programs also, not only for those investigators, 11 but for our program coordinators, those who are 12 involved in supervising FDA research, and also in our 13 own institutional review board, because we do have 14 one, of course, that oversees projects that are either 15 sponsored by FDA or conducted by FDA personnel. So, 16 I can talk a little bit about how we've approached 17 that, but that's not the international arena. So, I 18 want to turn away from that a bit and we can bring 19 that up in terms of questions. 20 I have to also remind that we don't have 21 legal authority or jurisdiction outside of the United 22 States. We cannot impose on other countries how 220 1 ethics needs to be approached or how ethics training 2 needs to be approached. We can certainly try to 3 leverage in that area and that is part of our 4 international strategy. Where we have authority is 5 simply in the ability to set conditions for accepting 6 non-U.S. data that will be used in support of either 7 research permits or marketing permits in the United 8 States for the U.S. population. And that is certainly 9 significant leverage, but it is not the same as direct 10 sponsorship, it is not the same as direct legal or 11 jurisdictional authority. 12 I have to remind people that FDA can 13 accept studies in two ways because this becomes very 14 significant in terms of how we can impact in the area 15 of investigator education and training. 16 We can, in fact, encourage, and we have 17 done that on occasion, sponsors to come in to FDA and 18 voluntarily put themselves under an FDA 19 investigational new drug application, that is, to 20 voluntarily say that they are going to follow all FDA 21 laws for studies that are conducted outside of the 22 United States. But we have no jurisdiction to force 221 1 that. There is no way we can impose ourselves on 2 international studies. But we can, in fact, encourage 3 that kind of voluntary development. 4 Now, if that is the case, if a sponsor 5 voluntarily says we will do our studies outside of the 6 United States under an IND, then all FDA regulations 7 have to be followed. And these include some very 8 specific regulations, including attestations from 9 investigators that they are qualified, that they 10 understand the basics of good clinical practice, that 11 they will carry these out. 12 Most non-U.S. studies come into FDA under 13 another set of regulations by which we can accept 14 completed studies. We can accept these because, 15 again, they may be very important for advancing the 16 public health in the United States. That was the 17 philosophy behind providing such regulations. And we 18 can develop regulatory requirements for such 19 acceptance. But, in most cases, we are, again, 20 talking about completed studies. So, it's not a 21 leverage, typically, in real time, it's a leverage 22 after the fact. 222 1 Now, let's go back to the issue of FDA 2 investigator training. Under our IND regulations and 3 also under our regulations for accepting non-U.S., 4 non-IND studies, we have very general guidelines, 5 general regulations, that say you need to be qualified 6 or that you need have -- be qualified by education, 7 training, and experience. But that is as explicit as 8 the regulations get, they don't specify a single core 9 curriculum, they don't say what your level of specific 10 ethics training must be, nor do they set out a set of 11 core competencies, either on a broad level, or 12 specific to that particular clinical trial. But they 13 do, in fact, put responsibilities and develop this 14 concept of good clinical practice. Good clinical 15 practice embraces basic applied ethics. 16 And, largely, that's what we're talking 17 about when we're talking about FDA oversight. We're 18 not talking so much about didactic ethics training as 19 we are talking about the application of ethics, as I 20 think Bob Levine mentioned, in kind of a procedural 21 sort of viewpoint. 22 So, in any case, under our regulations, 223 1 study sponsors do have responsibilities here for 2 selecting qualified investigators, for providing them 3 with the information they need to conduct an 4 investigation properly, and for proper monitoring of 5 the investigation. And, as I say, this is kind of a 6 segway. I hope to have some discussion of how 7 industry does what they need to do to meet this basic 8 regulatory requirement. 9 Now, as far as ethical conduct of 10 research, under the IND, if you look at GCP, if you 11 look at GCP, if you look at IND regulations, they 12 provide many procedural examples of how ethics needs 13 to be put into place in principle. Issues relating to 14 informed consent, review by an independent board, 15 privacy confidentiality, even some issues related to 16 financial interests. 17 For non-U.S. non-IND studies, which is the 18 bulk of what we get internationally, currently we are 19 still very vague in what the requirements happen to 20 be. The current regulations are still linked to very 21 old versions of the Declaration of Helsinki, as a 22 minimum standard, and our proposal, one that has 224 1 already gone out for public comment, and is shortly to 2 be finalized, is to link to internationally recognized 3 GCP standards, so, in fact, to set the floor, similar, 4 internationally to what we have in the United States. 5 Now, let's then turn, very briefly, to the 6 issue of ethics committees, because I think is 7 something that we also need to discuss here. First of 8 all, even when we're talking about ethics education, 9 in large measure, there is no regulatory requirement, 10 either from OHRP or from FDA, that says an individual 11 who serves on an ethics committee has to have any 12 basic ethics training. That is not part of what 13 regulations address. And, in fact, what the IND talks 14 about is that an investigator must use an IRB that 15 meets all FDA requirements, unless a waiver is 16 granted. So, we're not addressing the issues of 17 education or training anywhere in our regulations. We 18 are simply dealing with issues such as membership, 19 such as operation of the IRB, and that's in the U.S. 20 So, as we go internationally, it becomes 21 even more vague. If we're looking at what our 22 regulations currently state right now, in these 225 1 references to the old versions of the Declaration of 2 Helsinki, we are talking about terms such as when the 3 research has been approved by an independent review 4 committee. Does that mean an ethics committee as we 5 currently think it's constituted? Not necessarily. 6 So, what we are proposing, certainly, as 7 we move GCP regulations, is some explicit references 8 in regulation to independent ethics committees and to 9 what their interpretations should be, to requirements 10 that these ethics committees have to review and 11 approve the study before initiating it, which 12 currently regulations for accepting non-U.S. non-IND 13 studies don't currently address. And also, the 14 continuing review by an ethics committee is part of 15 the expectation. 16 So, as far as where we're going, right 17 now, internationally, there's not a lot of information 18 or a lot of explicit requirements that are in place 19 with training either of the investigators of the 20 ethics committee. What we are moving toward is a 21 situation where we are defining more explicit 22 requirements, but again, not specific for curricula, 226 1 and requiring some level of documentation to show that 2 these standards have been met, asking how 3 investigators were trained, how informed consent was 4 obtained, information about the qualifications of 5 members of ethics committees, information about how 6 the sponsor monitored the study. 7 So, these are the directions we are going 8 in. And we are hoping that, in fact, by moving in 9 this direction, of asking for and getting more 10 explicit information, we may have some of the 11 benchmarks to be able to look at where to go in the 12 future, as well as to assess where we need to, 13 perhaps, put our inspectional energies. 14 As far as inspections go, we've been 15 inspecting, again, for about 26 years internationally, 16 our authority to inspect is imbedded in the IND 17 regulations. We've done over 600 non-U.S. inspections 18 in nearly 60 countries. We continue to assign 19 anywhere from 36 to 60 per year and the list of 20 countries continues to grow. It's certainly becoming 21 much more global, reflecting the industry as a whole. 22 But again, as we look at these, what we do 227 1 on our inspections, we do ask very basic questions 2 about investigator qualifications and GCP training. 3 Now, what if -- how do we assess this? Well, in large 4 measure, the way we are able to assess this is based 5 on, one, are there deficiencies? If there are 6 deficiencies, then we can kind of go back and try to 7 reconstruct, are those deficiencies related to 8 deficiencies in education and knowledge, are they 9 deficiencies related to compliance and the ability to 10 behave, according to what you already know. And 11 that's really where we are in all this. We don't 12 generally inspect U.S. ethics committees, and that's 13 an issue as well, but it can be a condition of FDA's 14 accepting international data. 15 And again, as we look at metrics, if the 16 question is asked, how about the application of GCP, 17 internationally versus domestically? As we have 18 started to articulate broad international standards, 19 the differences have really minimized. We don't see 20 large differences in terms of meeting these specific 21 issues and requirements, as they are embedded in our 22 regulations, between non-U.S. and U.S. sites. The 228 1 differences are increasingly small. 2 This takes us a little bit to where we're 3 going. As I said, a good part of what we've seen over 4 the past few years is that, by developing standards in 5 an international environment, it in fact takes into, 6 as part of the development, documents, as well as 7 stakeholders from all ends, we're having more success 8 in at least, again, achieving this level of compliance 9 with applied ethics as part of GCP. 10 To us, this is I a big part of where we're 11 putting our energy. In the next two or three months, 12 a guideline, or a handbook will come out from the WHO 13 dealing with implementation of GCP for developing 14 world audience that's built off the CIOMS' guideline, 15 that's built off of ICH. This is the kind of thing 16 that we think will help develop and further education 17 of ethics and GCP. 18 A second area, again, of course, we 19 maintain the responsibility on the sponsor to educate, 20 but we also, recognizing that we don't have 21 jurisdiction outside of the United States, one of the 22 best ways for us to leverage and to promote ethical 229 1 conduct in ethics training is to get other regulatory 2 authorities on line, growing, developed, and looking 3 at clinical trials. So, a lot of our attention of the 4 past two to three years has been working with 5 regulatory authorities that want to develop oversight 6 programs. In the past few years, this started with 7 Canada, Australia, more work with Japan and the EMEA, 8 more recently, Singapore, Jordan, Israel, and now, in 9 the past year, India and China. And we think this is 10 a very good way to promote education and the movement 11 of ethics. Information sharing among regulators as 12 well. As we start to share the kind of reports that 13 other regulators are developing, as they look at 14 clinical trials, and we see where there may be 15 difficulties on an ethical level, we can use that as 16 a basis for conversation with those authorities and in 17 the development. 18 So, as we -- again, a lot of our focus is 19 at the sponsor and at the regulator level, and 20 finally, trying to do some targeted education and 21 outreach. And that's really how we've approached this 22 at FDA and I think, as you'll hear, industry and 230 1 others involved in FDA regulated research have 2 responded to move these kinds of initiatives in their 3 own way as well. 4 So, I thank you very much. 5 (Applause.) 6 DR. LEVINE: Thank you very much, David. 7 Are there are any questions for clarification? Ernie? 8 CHAIR PRENTICE: First, a comment and then 9 a question. 10 Bob, I'd like to invite you to be the 11 moderator for all of our panels because, so far, 12 everybody's been on time. That never happens to me. 13 (Laughter.) 14 CHAIR PRENTICE: Now, for the question. 15 David, you mentioned the reference to the old versions 16 of the Declaration of Helsinki. In your revised 17 guidance, is it the intention of FDA to totally 18 eliminate any reference to any version of the 19 Declaration of Helsinki? 20 MEMBER LEPAY: The answer to that, as 21 regulation, is yes. The answer to that, in practice, 22 is no. Because the first line of the good clinical 231 1 practice in ICH, and the WHO, and the PAHO good 2 clinical practice guideline makes direct reference to 3 ethical principles in the Declaration of Helsinki. We 4 think that's the appropriate approach, that we are not 5 linking to a specific document, but we are rather 6 linking to the principles that underlie that document 7 which are also common to good clinical practice. And 8 that's how we think the regulations should most 9 appropriately reference. 10 CHAIR PRENTICE: Okay. Thanks. 11 DR. LEVINE: If I may add a comment on 12 that? All the international documents make reference 13 to the Declaration of Helsinki. However, after having 14 first made reference to the Declaration of Helsinki, 15 then they systematically provide recommendations that 16 are in direct conflict with the apparent requirements 17 of Helsinki. And when I saw FDA publish its proposal 18 to purge that Declaration from its regulations, I 19 wanted to celebrate that. I don't know how much 20 further you can carry that because, as you point out, 21 David, they always continue to make reference to this. 22 But, if you follow that, you're going to have some 232 1 interesting times figuring out whether placebo 2 controls are ever justified, among other things. 3 MEMBER LEPAY: Among many other things. 4 DR. LEVINE: Our next speaker will be Jean 5 Louis Saillot. Dr. Saillot is vice president and head 6 of global pharmacovigilance at the Schering-Plough 7 Corporation. Dr. Saillot is also regularly involved 8 in various activities of the PhRMA Organization, 9 activities related to pharmacovigilance, clinical 10 research and ethics. He is currently the chair person 11 of the PhRMA Clinical Research Technical Group and a 12 member of the PhRMA Clinical Leadership Committee and 13 of the Pharmacovigilance and Epidemiology Technical 14 Group. 15 Jean Louis? 16 DR. SAILLOT: Well, thank you, Dr. Levine, 17 or Bob. 18 (Laughter.) 19 DR. SAILLOT: I would like to take the 20 opportunity to thank Dr. Schwetz, Dr. Prentice, 21 obviously, Bob, and the committee for giving me the 22 opportunity to say a few years. It is an honor and a 233 1 privilege to share on the panel, a meaning experience 2 as well, in the presence of Dr. Levine. 3 What I would like to do is provide the 4 committee with some background as to what are the 5 drivers driving sponsors to do clinical research in 6 different parts of the world. I will try not to go 7 too much in depth into this but move on to some of the 8 practices that are followed by sponsors. And you will 9 see that I will focus on the basic, the basic minimum 10 requirements that are driven by international guidance 11 documents, such as the International Conference for 12 Harmonization good clinical practice document. And a 13 lot of what you will hear will resonate to the 14 presentation that Dr. Lepay made in terms of 15 fulfilling global regulatory requirements. 16 It will probably not go in as much depth 17 in terms of the training, the ethics training, 18 particularly beyond the sponsor's personnel or the 19 investigators but you will see the current status of 20 things and, hopefully, this will be a trigger for 21 questions or discussion during the panel. 22 So, with this said, I would like to 234 1 briefly go over the drivers for pharmaceutical 2 industry international clinical research, the current 3 state of the, basically, research internationally and 4 some of the challenge and opportunities. 5 What is an overriding principle on 6 industry sponsored trials is the need for global 7 approaches, basically, applying a standard that will 8 allow for research to be conducted throughout all the 9 countries that are involved. The clinical development 10 programs are global in nature. The goals of the 11 industries provide the scientific evidence based on 12 clinical research of the value of a new product that 13 is targeted to be put on the market, but this dossier, 14 the dossier that is created, is really targeted to be 15 available worldwide to all regulatory authorities. 16 That does bear in mind, in terms of the standard, that 17 by default gets applied. That is, any kind of 18 activity that is done globally will make sure, the 19 sponsor will make sure that the standards would allow 20 for the dossier to be acceptable by the FDA, thereby, 21 whether under the IND or not, and I may speak a little 22 bit more about this, by default, the same standards 235 1 are being applied. 2 So, it's an important point that the 3 committee and the panel should keep in mind. I don't 4 think I need to go in terms of the complexity of 5 clinical research and access to certain population and 6 disease that may be drivers for participation or 7 conducting clinical trials outside of the U.S., as 8 well as a very important need or expressed interest in 9 different countries around the world to be part of a 10 clinical development programs. 11 I will not go in terms of a lot of details 12 on this, just to give you, and this is illustrated, 13 this is based on my informal polling of some of my 14 colleagues, but to give you an example of how clinical 15 research is being distributed, if I could say so, 16 across the world in a typical large industry fashion. 17 It's still, the majority of trials that are done 18 within the U.S., when you combine with the European 19 Union, the vast majority of trials are being conducted 20 in these regions with a proportion varying from 10 to, 21 you know, 40 percent, roughly a third of the 22 activities being conducted outside of Europe and the 236 1 U.S. 2 I will go very briefly over this because 3 I don't think that it is really relevant to today's 4 topic, which is about training, ethics training and 5 capacity building. Just to take home a message that 6 doing clinical research internationally is not always 7 easy. There are aspects that need to be weighed very 8 carefully, including the methodology of the trial, the 9 homogeneity of the patient population, difference in 10 medical practice and all of the complexity that, you 11 know, have been highlighted in the context of 12 international clinical research. 13 Some of the critical factors. I think 14 that this is a good segue. Again, I did mention that 15 a little earlier in my introduction, but very 16 important factors that drive activities by sponsor is 17 really the acceptability of the research by all 18 relevant health authorities, including the FDA. 19 So, in practice, all global clinical 20 development programs are based on full compliance with 21 the ICH, again, International Conference on 22 Harmonization, good clinical practice and a number of 237 1 this guideline is well known by, I assume, by most of 2 you, is number E-6. The way that the sponsor 3 fulfilled their obligation of, and I have a mention of 4 that later on, is through training, but also 5 monitoring, quality assurance, and selection of the 6 investigator with the appropriate credential and 7 experience. 8 A word on IND versus non-IND studies. I 9 think that the difference, if there are, and my own 10 experience is that studies are done on an IND basis, 11 globally, other companies may have different 12 approaches, but the take home message here is whether 13 it is under an IND or a non-IND, the same global 14 standards are being applied. The constitution of the 15 ethics committee and the institutional review board is 16 part, an underpinning, if I could say so, of the good 17 clinical practice. And there are some differences 18 between an IND and non-IND which are more procedural 19 in nature. 20 And, for lack of a better term, the 21 wording is pretty poor, I couldn't come up with 22 anything better, but the new room for error factor is 238 1 really to portray that a company going into a very 2 significant investment in doing research for a new 3 product, there's the underlying importance to make 4 sure that the data that comes from the development 5 program would be acceptable by all relevant regulatory 6 authorities. It may be a backdoor way of explaining 7 how FDA has actually much more leverage than what Dr. 8 Lepay had mentioned. Because even though it's not 9 under an IND, the same standards basically apply. I 10 hope that this makes sense. We can, you know, expand 11 on that further, as needed. 12 I think I'd rather switch now to the mode of 13 operation, which may be a little bit more close to the 14 questions that Dr. Schwetz had in terms of what does 15 the sponsor, the pharmaceutical industry, do in terms 16 of training. And during the teleconferences in 17 preparation for this panel, I basically said that it's 18 a bit humbling to see that the contribution of 19 sponsors is very limited, actually, very limited to 20 the training compared to some other initiatives, you 21 know, such as what Melody has mentioned earlier on. 22 But the focus of the training is really on the 239 1 sponsor's personnel and the investigators. And, I 2 think Dr. Lepay mentioned, you know, this is, and I 3 will expand on this, it is a responsibility of the 4 sponsor shared with the investigator for the 5 production of clinical trial subjects, together with 6 institutional review board and independent ethics 7 committee. 8 So, there is quite a bit of investment, if 9 I could say so, or training investment that is being 10 made for the personnel, the sponsor personnel, such as 11 monitors that go and visit the sites on a regular 12 basis, as well as the investigators. And I have a few 13 examples of this. 14 There are very important, and to go back 15 to the top of the slide, very important ethical 16 principles that are published trainings and 17 communicated within the companies. They have 18 different names. The PhRMA group of companies has put 19 together principle of conduct of research study and, 20 actually, modesty was involved in the writing of this 21 document, but a lot of companies have internal codes 22 of ethics, credos, however these are labeled, that are 240 1 being trained to the monitors and to the people in 2 charge of the programs. 3 I think we briefly talked about it, the 4 fact that the ICH good clinical practice has its 5 foundation on ethical principles on the Declaration of 6 Helsinki. You know, obviously, some of the elements 7 of the new version of the Declaration of Helsinki, 8 particularly with regards to placebo, makes it, you 9 know, a bit of a challenge in terms of the actual 10 implementation. And I don't know whether we will, you 11 know, have to touch on this. It's not really related 12 to training of ethics, but I am sure that if Bob wants 13 to bring this at the panel discussion, we could do 14 that. 15 I think that this slide is probably the 16 most relevant to today's discussion. What I wanted to 17 share with you, what happens, in terms of training of 18 monitors or investigators, is pretty standard 19 throughout the industry. There is a curriculum, there 20 are SOPs that basically proceduralize the requirements 21 of GCP and the principle of ethics protection, or the 22 ethical principle behind the protection of patients 241 1 within clinical trials. And all the monitors, you 2 know, any company would be trained and quite 3 significantly in terms of understanding all these 4 requirements. 5 We also, as sponsors, have quite a large 6 impact on investigators and there are different media 7 that are being used. For example, a typical study 8 would have what is called an investigator meeting, 9 which is to go over the protocol for all the 10 investigators included in the sites. Very frequently, 11 and I can't think of any such investigator meeting, 12 there is a significant proportion of the time that is 13 to go back to the actual conduct of the study with 14 regard to GCP and ethical expectations during the 15 study, as well as training, for example, and reporting 16 of adverse events and safety issues. This is a fairly 17 standard way that this training is provided to 18 investigators and, in that sense, there is some level 19 of capacity building. But, again, it is modest 20 compared to the entire spectrum of activities that 21 folks are involved in and maybe sponsors should be 22 more involved in. But we may take this during the 242 1 discussion part of the presentation. 2 Also, beyond the investigator meeting or 3 initiation meetings, there are visits that are being 4 made by the monitors that basically look at the way 5 that the study is conducted and it's both an 6 oversight, as well as a training function. Whenever 7 there are things that are not done according to the 8 protocol, according to the procedures of the ethics 9 committee are not being followed, it is the role of 10 the monitor to, basically, highlight this to the 11 investigators and, sometimes, actually to the ethics 12 committee or the IRB, should there be repeated 13 deficiencies at the level of the investigators. 14 So, there is this role of site initiation 15 visit, in terms of education, but also, didactic 16 ongoing monitoring visits also play a role. There is 17 also a number of checks and balances, including 18 quality assurance, which is independent from the 19 monitors that also visit the sites and have a role 20 there. 21 I would like to conclude. I don't want 22 to, you know, go too much overboard or overtime. 243 1 Just to conclude, on the slide for a change in 2 opportunities. Conducting research internationally 3 is, indeed, very complex. It is a very dynamic 4 environment. There are, in terms of the complexity 5 for sponsors, is to be able to deal with not only the 6 global standards, as well as the local standards, 7 standards that are particularly difficult to implement 8 our standards associated with the different privacy 9 regulations that sometimes may be in conflict with 10 other regulations. For example, on safety reporting, 11 it's always a fine line to walk. 12 I did mention the very dynamic 13 environment. There are differences in terms of the 14 level of experience of investigators where you can go 15 to, you know, a Latin American country in a large city 16 and you will, actually, not see much difference from 17 any site that you would find in the United States. 18 And then, or even, you know, Africa, Far East, and you 19 have a difference in terms of sites that may be 20 located in a more less, how could I say, build up 21 careers, for lack of a better term. 22 There may be differences as well in terms 244 1 of the companies and how companies operate. My 2 experience is with large companies. I don't have 3 experience with the device industry which may have a 4 different approach to things, but I would assume that 5 the good clinical practice principles would be applied 6 in a very similar way. 7 And I think that I will end on this, you 8 know, mention, again, humbling, I think, but also, I 9 think, that even me being able to listen to all the 10 suggestions from the presentation and the panel will 11 help in terms of listening to other opportunities. 12 But the industry training really, as a take home 13 message is more applied ethics than a formal ethics 14 training and education. 15 And with regard to international standards 16 for ethics, I mean, the mention of CIOMS, it is true 17 that if you ask folks within the industry, everyone 18 will know the ICH good clinical practice. Will they 19 also know the CIOMS guideline? Probably not as much. 20 So, there's effort that can be done even, you know, 21 within the industry in terms of going beyond ICH, 22 going beyond that, you know, you can label it minimum 245 1 standard or good starting point. And maybe if we 2 follow thoughts for Dr. Lepay in terms of referencing 3 international GCP standards. And, you know, I don't 4 know that the entire industry would be saying, oh, 5 great, you know, now we have yet another standard. 6 (Laughter.) 7 DR. SAILLOT: But, I just would like to 8 let the FDA not underestimate the power that they 9 have, given the fact that, again, sponsors have to 10 make sure that they prepare dossiers and they conduct 11 research in a way that FDA will feel comfortable with. 12 The last point is the rolling industry and 13 capacity building and potential conflict of interest. 14 I mean, there were a lot of great points in terms of 15 where sponsors may be going further than what I just 16 described. And the balance is, you know, how would it 17 be felt for a sponsor to be funding the education of 18 an independent ethics committee? Would that be 19 considered a conflict of interest or not? I don't 20 have the answer to that, I just would like to put it 21 out there on the table for the panel discussion. And 22 with this, I will stop. 246 1 (Applause.) 2 DR. LEVINE: Thank you very much, Jean 3 Louis. Any comments or -- yes, please? 4 MEMBER JONES: I just -- you also point 5 out there are differences in company size but how much 6 crosstalk in terms of standardizing between companies 7 how to go about, should we be training, or other 8 ethics education? 9 DR. SAILLOT: There is some level of 10 interaction. It is not as formal as maybe it should 11 be but through PhRMA working groups, for example, 12 there is indeed a lot of cross-sharing of ideas. 13 There is a specific working group, which is called the 14 BioPhRMA working group, which is focused on quality 15 assurance ethics and I know that they do share. I 16 made a couple of presentations to this group, I don't 17 attend always, but they do share best practices. 18 There is also a fora, just like the DIA, 19 which also has a lot of good training on ethics, which 20 is attended, obviously by a lot of the industry, but 21 also by investigators more and more. There is other 22 fora like this, the Association of Clinical Research 247 1 Professionals, the American Association of 2 Pharmaceutical Physicians and Investigators, which, 3 you know, are pushing certification and training 4 agenda. We may talk about this later on. 5 Did I answer your question? 6 DR. LEVINE: I thought I saw another 7 hand. Yes, sir? 8 MEMBER POWELL: The question I had was, 9 most of the trials you are talking about really appear 10 to relate to the larger patient trials, Phase IIs, 11 IIIs, that are -- 12 DR. SAILLOT: Right. 13 MEMBER POWELL: -- part of the marketing 14 application. Are there any differences that you've 15 seen related to the early phase trials, such as Phase 16 I, proof of concept studies? 17 DR. SAILLOT: Actually, the differences 18 may be more -- well, the Phase I studies are very 19 specific in terms of the size being much smaller, the 20 technical requirements being much higher. Conducting 21 -- you cannot conduct Phase I everywhere, clearly, 22 nothing that, you know, there's no issues that you 248 1 don't need to worry about Phase II, III and IV. But 2 they're so specific that, usually, in my own 3 experience, proof of concept and Phase I studies are 4 really traditionally made in either the U.S. or 5 Europe. Very rarely, in other countries. And that's 6 probably because of a level of comfort that folks, you 7 know, know, have worked within sites, or academic 8 institutions or centers that they have experience with 9 and would feel less comfortable, you know, expanding 10 their research. 11 I don't know that I answered your 12 question, though. Not completely. 13 MEMBER POWELL: Well, I think, probably 14 some of it tends to operate outside of the regulations 15 or the ethics issues, to some extent. For instance, 16 Phase I studies that are conducted in places -- a 17 while back they were conducting in places that really 18 only had a site committee review and that was it, but 19 I guess that's changed in recent years. 20 But, the reason I asked the question is, 21 there's a lot of various standards, perhaps, with 22 respect to how each one of these types of sites really 249 1 operate with respect to the requirements. 2 DR. SAILLOT: No, I would say that the 3 requirements, at least in my experience and with the 4 colleagues that I have talked to, are very consistent 5 across the board. The difference in the early phase 6 is really methodology, it's volunteer as opposed to 7 patients. These are very significant difference, you 8 know, in terms of the methodology, but the underlying, 9 you know, for example, the standard operating 10 procedures, are the same. You know, there's no -- 11 there's not really a difference between a Phase I, 12 Phase II, or III in terms of monitoring requirements 13 and all the SOP requirements, same. You know, instead 14 of having an investigator meeting, you know, you may 15 just have a site initiation because you 16 have a single site. These are the differences but I 17 don't -- I'm not aware of a very significant 18 difference in terms of the foundation of the 19 requirements. 20 DR. LEVINE: Let me say that it seems that 21 we're moving beyond clarification into substance and, 22 while I'm very interested in the substance, I do want 250 1 to make sure we get all of our speakers in and have a 2 good time left for discussion period. 3 The next presentation you will hear has 4 two collaborators in it. One is Karen Hansen. Karen 5 is the Director of the IRB office at the Fred 6 Hutchinson Cancer Research Center in Seattle. She has 7 also contributed to the planning and presentation of 8 numerous local, regional, national, international 9 training and networking programs. These include 10 programs that she participated in presenting in such 11 places as Botswana, Malawi, Durban, Dominican 12 Republic, Haiti, to name a few. 13 The author of this presentation is Maureen 14 Power and Maureen will be the speaker. Maureen has 15 been at the National Institute of Allergy and 16 Infectious Disease since 1990, working with funded 17 investigators performing clinical research in HIV, 18 AIDS, tuberculosis, malaria, other HIV associated and 19 tropical infections. Her particular interests include 20 developing clinical research capacity within 21 institutions, both in the United States and abroad, 22 including planning for and training new personnel and 251 1 developing systems for the orderly conduct of clinical 2 research. She has had multiple experiences, both in 3 South America and in Africa. 4 We knew we wanted each of these two people 5 to be part of our panel, but asked them to decide 6 which one would present the formal presentation and 7 Maureen was selected. Maureen? 8 MS. POWER: Thank you very much. I want 9 to take this opportunity to thank Dr. Prentice and Dr. 10 Schwetz and, of course, you too, Bob, for the 11 privilege of coming and speaking about our IRB 12 capacity training activities that we have undertaken 13 at the NIAID and in conjunction with the Fred Hutch 14 Cancer Research Center. 15 Just for a second, to connect those dots 16 for all of you and to add another dot to it, the Fred 17 Hutch Cancer Research Center in Seattle, as well as 18 the Family Health International in North Carolina, 19 serve as operations offices and/or data management 20 centers for several of the data sponsored HIV/AIDS 21 clinical trials networks. And so, to say that we 22 have, we're very international focuses of vaccine and 252 1 prevention research. And so, to say that we have 2 similar interests is not true. We have very acutely 3 shared interests. We share similar problems often and 4 similar challenges. And so, it's been very pleasant 5 to work with both Karen and David, who has just walked 6 in the room, in many of these capacity building 7 activities. 8 I just want to give a little bit of 9 background and say that NIAID has been increasing its 10 international research portfolio in recent years and 11 I would say that that is largely related to its own 12 commitment and its commitment with other partners to 13 reducing the morbidity and mortality associated with 14 the major infectious diseases over the years. And 15 this is, of course, we're involved in many, many 16 global partnerships in this endeavor. And, in the 17 recent years, clearly, the international research 18 portfolio has grown considerably. 19 And, as other people have pointed out 20 here, along with the growth in a portfolio like that, 21 there's also an increases in many of the ethical 22 challenges and that situations can become very complex 253 1 sometimes. 2 At our international locations, we find, 3 of course, a variety of situations. There's no, you 4 know, single norm that one can describe. But, very 5 often, what you find is that there is sometimes a very 6 limited understanding of U.S. requirements. And not 7 only is there a limited understanding of some of the 8 requirements, but there is also, often, a limited 9 access to information and guidance. I think that we 10 all forget what it was like before we had, you know, 11 hard DSL lines and were instantly able to go online 12 and collect information and gather opinions very 13 quickly. And people are, often, in really rather 14 remote locations, are not sure where to turn for 15 guidance. 16 Contemporaneous with all of this, I also 17 just want to mention, because I think it helps spur 18 some interest in IRB capacity building at the NIAID 19 was that the FWA process, when it was initiated a few 20 years ago, had a big impact on how we reviewed the 21 international research. Most of the international 22 research was done through single project assurances, 254 1 largely. And so, when those started to be phased out 2 and our institutions moved to FWAs, you realize that 3 we lost a critical and a very important part of the 4 review process that was going on at OPRR or OHRP. And 5 I'm not making a negative comment here, I'm just 6 saying that we were aware that the landscape was 7 really changing for us, at that point in time. 8 So, around 2001, I think, was the first 9 time that someone at NIAID embarked on a research 10 training activity that was specific to ethics and it 11 was a workshop that was conducted in Malawi called 12 Ethical Aspects of Clinical Research. The energizer 13 behind all of this was one of my colleagues, at NIAID, 14 Dr. Elizabeth Higgs, and she worked with the clinical 15 center bioethics department, Dr. Emanuel's group, whom 16 I'm sure many of you are very familiar with, and they 17 put a four-day workshop in Malawi that was widely 18 attended. There were 70 or 90 members or participants 19 at that activity. It was very, very well received. 20 And, since then, of course as you probably 21 all know, Dr. Emanuel and his group have done a number 22 of other presentations, which I would say are 255 1 fundamentals of ethics as applied to clinical 2 research. It's about a four-day workshop, very 3 interactive. And they've done a number of workshops, 4 some of which have been done in collaboration with the 5 National Institute of Allergy and Infectious Diseases 6 and others that have not. 7 The audience for these training programs is 8 widespread, individuals, local individuals, who have 9 an interest in clinical research. And so, you have 10 investigators attending these, as well as IRB members, 11 chairs of IRBs, institutional officials, etcetera. 12 So, it's a fairly wide group. 13 In talking with people and trying to set 14 up IRBs in Africa, working with some of our regional 15 partners, I began to understand that there was a 16 desire to see something a little bit more focused on 17 IRBs. And so, I think it was in 2002, we, Dr. Emanuel 18 and his group, did a workshop in Ghana, in Accra, one 19 of these four-day workshops, and we attached to it, 20 the PRIM&R IRB 101, modified a little bit for the 21 setting. And Dr. Bob Levine was one of the presenters 22 at that session. 256 1 So, I think that the take home message, 2 and as I focus my talk, I'm not going to focus on, you 3 know, understanding the principles of bioethics as 4 much as how that relates to developing functional 5 institutional review boards. And much of the training 6 activities that we have undertaken have to do with 7 trying to build capacity within the IRBs in order to 8 get their work done. 9 So, that, I guess that the first thing I 10 would say is that the bioethics education, such as, 11 provided by Dr. Emanuel's group, or Barbara Sina will 12 be talking next and talking about the Fogarty 13 programs, are very critical. I think that it is just 14 essential in order to have effective IRBs in these 15 international settings but I would also say that it's 16 sort of necessary, but not sufficient. And there are 17 a few other needs that were identified. And I think 18 one of the important ones which several of the members 19 or the panelists already have really emphasized, is 20 that training needs to be ongoing, that it's not a 21 one-shot deal and that you have to find sustainable 22 training activities that can be repeated. 257 1 There was, in fact, an interest amongst 2 some of our colleagues in Africa to develop a workshop 3 that would be specifically for the institutional 4 review boards. And, over a period of about a year or 5 two, we talked and had a number of meetings where we 6 talked about what the curriculum would be, we sought 7 input in a variety of locations, we had meetings that 8 OHRP members attended, we talked other sponsors of 9 research, other parts of the NIH, and we also had 10 conversations with many of the target audience in 11 Africa, members of IRBs and the chairs of IRBs. And 12 so, this list of needs that you see on this slide and 13 the next slide, are not scientifically derived, but 14 rather based on the results of a number of these 15 conversations. And I've tried to put them in what I 16 think is an appropriate order. 17 This is what people were telling us that 18 they were having difficulties with. They're having 19 difficulties interpreting and implementing 20 regulations, directives, guidances, whether it be the 21 U.S. directives or anyone else's. They just had 22 trouble moving from the normative to the substantive 258 1 to the procedural. They had trouble writing and 2 implementing standard operating procedures that would 3 guide the work of their institutional review boards. 4 There's a lot issues around the management 5 or people working paper. The whole process of this 6 institutional review board, I think, is very foreign 7 in many foreign settings. And that running effective 8 meetings was an issue that came up frequently, being 9 able to figure out how to divide up the workload of 10 the IRB so that it could be effectively performed. 11 Paper, just imagine, in some of these resource limited 12 settings, I can tell you they are copying protocols 13 this thick, making 15 copies and getting them 14 distributed to a variety of people in a reasonable 15 amount of time is a very serious hurdle in many of 16 these resource limited settings. So, they have a lot 17 of additional challenges to what we always think 18 about. 19 Something else that's very important is 20 that they need to develop local training programs for 21 their own investigators and their students, in order 22 to help to develop an appropriate culture within their 259 1 institutions related to ethics and IRBs, and that's a 2 concern for them. And this, of course, varies from 3 place to place, but many of the resource limited 4 settings have really a paucity of their own local 5 regulations and guidance and they're very reliant on 6 ours, which don't always fit their needs perfectly. 7 And so, many of them expressed a need to be able to 8 think through and sort of work and develop their own 9 approach to handling issues and research. 10 Some additional needs of IRBs that we 11 identified is that there really has to be 12 institutional buy-in. I think that that's probably a 13 given here in the United States, but it's often 14 difficult in situations where the IRBs are relatively 15 new for them to have the appropriate level of 16 importance within their own institutions and support 17 of the institutional heads, for instance. They need 18 to have some community engagement and support. And I 19 think very important, they need to be able to network 20 from one IRB to another, from one setting to another. 21 These are often very remote areas, even in large 22 cities, and you look around and there aren't other 260 1 IRBs down the street. There's nobody that you can 2 readily call. You own IRB, you know, it's fairly new 3 IRBs that don't have a lot of experience themselves. 4 And so, there's a real need for people to be able to 5 network in order to get advice and support for what it 6 is that they're trying to do and to approach some of 7 their problems, in a common way. 8 And they also need access to resources. 9 And we haven't touched upon that too much today but, 10 it does take money to manage an IRB. So, there's then 11 issues of financial resources. They need, as I 12 alluded to before, information. It's not always 13 accessible, they don't always know where to get it 14 and, they need places where they can seek advice. As 15 you know, many of the issues are, in fact, very 16 complex and it's difficult for fairly new IRBs to wrap 17 their heads around some of the problems that they're 18 confronted with in the clinical research projects that 19 they're reviewing. And they need methods to 20 communicate. 21 So, there's a big list of needs. We have 22 tried to handle this, Karen and I, and others, in 261 1 three different ways. And so, I'm going to take them, 2 sort of, one by one. And the first one is just to 3 provide training opportunities in the United States, 4 to bring selected individuals here to the United 5 States and afford them opportunities. Another is to 6 have local and regional training in their host, in 7 their own regions. And the third is web-based 8 approaches. 9 So, training opportunities in the United 10 States. I landed on this a few years ago and realized 11 right away that it was a very effective thing to do, 12 was to bring people to the annual IRB meeting at 13 PRIM&R and ARENA. And between the Fred Hutch and the 14 NIAID, I think, and other people have sponsored. FHI 15 has brought people, too, and a few other 16 organizations. I know that we've sponsored more than 17 90 participants to attend this meeting, at one time or 18 another over the last five years or so, since 2000. 19 I think that this has, actually, served a 20 very useful purpose. As all of you know, you can 21 approach learning at this meeting on many different 22 levels and so, there's always something for everybody 262 1 there. And they often come out with some very, very 2 practical information. Something that I think is very 3 important is that there's, that I've seen on a number 4 of occasions in conversations with people while 5 they're at the meeting and then after they've attended 6 at the meeting, is that it makes all of it very real. 7 I think that, largely, a lot of our 8 foreign IRBs, foreign investigators, you know, 9 perceive all of this that people are telling them that 10 they need to do as some stuff, some gobbledygook, from 11 a bureaucratic place some place else. And they just 12 don't have meaning to it. I also think to myself that 13 it's like the pieces of paper that fall out of my 14 credit card bills every month. And you pick it up and 15 it says, you know, this is the card member's 16 agreement, and it's in font two and it goes on for 17 pages and pages, and I never read it. I don't know if 18 you do, but I never do. And so, I think that 19 sometimes they think, sort of, at that level. So, 20 people come to the PRIM&R meeting, they're sitting 21 there and they're listening to people talk, and 22 struggle with issues, and exchange opinions, and argue 263 1 about things, and complain about things, and I think 2 it all makes it very real and they just don't feel so 3 alone anymore. So, I think it has been really a very 4 effective training tool. 5 It also helps them with contacts and 6 networking and probably, I think, some of you in this 7 room probably understand that they're interested in 8 contact with people here in the United States who can 9 help them with problems in their institutions and to 10 forge some of these relationships. And people from 11 resource limited settings, from the same continent or 12 from other continents, need to network themselves and 13 sort of share information and that's been very 14 helpful. 15 Something else I think is that as the 16 numbers of people that we have supported at this 17 meeting have increased. I think that have sort of 18 reached a critical mass a year or two, they became 19 very influential in the discussion of international 20 research at PRIM&R. And I think the great example of 21 that was the workshop that was held the day before the 22 formal meeting last fall that was, largely, it was a 264 1 day-long meeting about international research, and was 2 largely moderated by Bob, but largely, and Jim Lavery, 3 but focused on regional speakers, describing 4 international research issues to an American audience 5 instead of vice-versa. And I think that that was very 6 helpful. 7 The other thing that we've done here in the 8 United States, which has been extremely helpful, too, 9 is had what I'm now calling IRB exchanges. Early on, 10 I sought assistance from IRBs that we had 11 relationships with in the Washington, D.C. area, and 12 we had people who were visiting in the country sit 13 through the NIAID IRBs and the U.S. Navy's IRBs and 14 sort of share information. Before the PRIM&R meeting 15 in San Diego, a number of individuals went to Seattle, 16 where Karen spent a lot of effort, and they had many 17 opportunities to meet with her IRB members and 18 investigators and people in the Seattle community. 19 And last fall, just before, the three or four days 20 before the PRIM&R meeting, we had about five different 21 sessions with IRBs that were attended by 5, 10, 12 22 international people. A number, some of you in the 265 1 audience were very helpful and that was actually 2 extremely helpful information. 3 So, what happens at these is that people 4 get a chance, sometimes, to observe IRB meetings as 5 they're working and hear what the deliberations are. 6 That's not always possible, but it's still very 7 helpful to have people meet informally with the chair 8 of the IRB or their administrators, which is every 9 important, members, investigators with an 10 international expertise, with an interest, and the 11 exchange information and advice. And I've sort of 12 italicized exchange, because it really is an exchange. 13 I think that if you talk to some of the people that 14 have hosted the IRB members, you'll find that they've 15 learned a lot, too, during the course of these 16 meetings, about what the realities are in some of 17 these international settings. 18 So, that's like what we've tried to do in 19 the United States. We also have some regional 20 trainings that we've organized and I think that 21 there's a couple of things that I want to talk about. 22 The first is country specific or IRB specific 266 1 training. Karen, through the Fred Hutchinson Cancer 2 Research Center, has utilized her enhancement grant, 3 her NIH enhancement grant, to reach out to a number of 4 the international IRBs in Botswana, Malawi, Haiti and 5 the Dominican Republic, and so she has provided some 6 ongoing support and initiatives for them. In order to 7 do this, she developed and implemented, she and her 8 team, a needs assessment survey, provided them with a 9 survey and then developed in-country training that was 10 based on the assessment, their own assessment of what 11 their needs were. 12 Some part of this that emerged through 13 these needs assessments, was the need to develop some 14 tools that IRBs could utilize to help them organize 15 their work. So, they did audit checklists and reports 16 and things like that. How to -- templates for IRB 17 minutes, you know, how it is, how you can capture 18 information so that you have thoroughly drafted IRB 19 minutes and checklists that people could use as they 20 were reviewing projects. Thing like this are 21 extremely helpful because, though they are 22 commonplace, I think, here in the United States, 267 1 they're pretty foreign in foreign locations. So, 2 that's kind of local issues and kind of IRB or country 3 specific. 4 The other thing that we did was we 5 organized regional training on a larger scale and we 6 called this the Partnership for Enhancing Human 7 Subjects' Protections, Helen McGough thought that term 8 up. And so, and the Partnership involved a number of 9 entities. It involved DAIDS, it involved PRIM&R, 10 PRIM&R was very helpful to us in this, also, the 11 University of Malawi hosted us in one year, KwaZulu- 12 Natal the next, FHI, Fred Hutch, and also the 13 University of Washington. And I put the Fogarty 14 International Center here, too, because we have relied 15 very heavily on trainees out of the Fogarty 16 International Center bioethics training programs that 17 you'll hear about next, as we developed this 18 curriculum. 19 And so, we had a variety of goals that -- 20 we had several goals. And the first one is that -- we 21 still have these goals, we haven't met all of our 22 goals yet. 268 1 The first goal is to develop a standard 2 curriculum for IRB training that would provide 3 fundamentals of U.S. regulations and international 4 standards, like CIOMS, that would offer practical 5 assistance and tools to the participants, like 6 templates, and examples, and slide sets that they 7 would be able to utilize in their own institution for 8 training, and that could be adapted to meet local 9 needs and interests. You know, things really do vary. 10 So, that was our goal one. 11 Goal two is to implement and refine the 12 curriculum and that's sort of where we are, at 13 implementing and refining the curriculum. And we also 14 want to be able to assess the impact, and we haven't 15 got a system for program evaluation yet. But, another 16 goal, once we've managed to refine the curriculums 17 more is that we would, in fact, like to make our 18 ethics widely available. So, we're always focused on 19 this as a sharing of knowledge. And all of our 20 participants have recognized that the information 21 would become available. 22 Oh, dear. I have to wrap it up. See, I 269 1 knew everybody was keeping on time, until they got to 2 me. 3 The other thing that we've really wanted 4 to do as a part of this, is encourage regional 5 participation and networking, as I mentioned before. 6 I think it's critical for these IRBs to learn how to 7 talk to each other and to have opportunities to do 8 that. 9 And the other goal that we had is to 10 provide opportunities for them to train and promote 11 the visibility of some of the Fogarty bioethics 12 trainees, whether they were trained at U.S. based 13 institutions or internationally. And so, we have 14 actually set up the curriculum so that it allowed lots 15 of speakers. 16 And so, I won't go through this because 17 it's in your slide set, that is, if you look at this 18 is like the content of these training programs, 19 agendas, you will see that it is, it's very concrete, 20 it's very practical and it's focusing on, it's 21 focusing often on the processes and the procedures of 22 getting that institutional review board's work done. 270 1 Having said that, with maintaining 2 throughout it a sense of the importance of the ethical 3 review process. We try not to get lost in the 4 procedures. In fact, actually, it's pretty difficult 5 to get lost in the procedures. People keep dragging 6 the conservation back, or bringing the conversation 7 back to the most important issues. 8 So, these are the kinds of things we talk 9 about, how to document the work, when you should 10 provide continuing review, etcetera. 11 I'll go through this very quickly, the way 12 that we've organized these sessions, just so that you 13 would know, is that we've kind of grouped topics into 14 two or three hour sessions, rather than have long 15 talks, we have very short presentations, often 10 or 16 15 minutes, and we utilize panel discussions a lot and 17 we use case studies. We always allow for substantial 18 discussion time, about half the time is discussion. 19 And we have moderators for each session that make sure 20 that the fundamentals are covered and that materials 21 are available. 22 Setting these up can be difficult. I 271 1 think, for the Malawi workshop, I had 27 regional 2 speakers for 10 and 15 minutes. So, the organization 3 of it can be a challenge. So, here's actually a 4 session from Malawi. See, we have a moderator from 5 the United States. 6 (Laughter.) 7 MS. POWER: And I won't go through this 8 example. I'll just say that, for instance, in the 9 session on scientific review that we did, we tried to 10 cover a couple of topics and we start with review of 11 ethical principles, and then we talked about how you 12 assess the scientific merit. People talked about U.S. 13 based institutional models for the review of topics, 14 like departmental review, because most of the, a lot 15 of the IRBs in resource limited settings are the only 16 group at that institution that's reviewing the 17 science, as well as the ethics. So, they often 18 function in a dual role. 19 And I won't dwell on this, but you get the 20 idea that we would have six or seven people presenting 21 short sentence, most of them being actual participants 22 in the workshop. And so, I also put this picture in, 272 1 so that you could see that sometimes our panel 2 sessions get very large. This would be a panel 3 session that had eight or nine people in it probably 4 talking. 5 The feedback from this session was 6 extremely positive. And I just wanted to spend a 7 minute, I know I'm running out of time, but -- I ran 8 out of time, is that it provided an opportunity for 9 the Africans. This is what they told us, that they 10 really appreciated the opportunity for them to present 11 and share material, for them to learn, and present, 12 and share material, rather than having the U.S. or, 13 you know, other Western partner doing most of the 14 training. It gave them an opportunity for networking 15 and it also gave them an opportunity to learn about 16 U.S. regulations. And this came through very loud and 17 clear, without being patronized. So, clearly, some -- 18 Bob, I think raised these issues of sensitivities at 19 the very beginning of his talk, and it clearly is an 20 issue, as we think about training, that we have to be 21 concerned about. 22 Let me see what I can do. So, we had a 273 1 follow up workshop after that, just to let you know, 2 that focused much more on developing local papers of 3 regional interest. And then, as a request from what 4 they had, we also had PRIM&R came back and helped us 5 and they did an adaptation of the administrator 101, 6 which we called PRIM&R -- yes, which we called 7 Research Ethics Committee 101 and Karen Hansen and Liz 8 Bankert were the faculty for that. And it took a day 9 and a half and the participation was just, the 10 evaluations were just, outstanding. People just need 11 this kind of very concrete work. 12 You want me to stop? Yes. 13 DR. LEVINE: I think, Maureen, you've 14 given us a very important look at what does this 15 education business look like, you know, on the ground, 16 so to speak. What it really, and I think people will 17 appreciate from reading the rest of your richly 18 detailed slides, it's not a formal uniform curriculum. 19 It's a bunch of people from the host country and from 20 an industrialized country getting together to form 21 relationships and figuring out how to make things 22 work. And I think it's a splendid model and I've been 274 1 delighted to participate in it under your direction, 2 and Karen's, and David's, Helen's. It's something 3 that I hope other people who it is new to will think 4 about, in some detail. 5 I will raise on objection to the acronym PRHPS. You 6 know what perps are. They're what, on the TV, that's 7 what they call the criminals. So, maybe we can work 8 something out on that. 9 Last, but not least among our speakers is 10 Barbara Sina. And we're very much devoted to Barbara, 11 or indebted to Barbara, devoted, as well, because we 12 asked her just to join the panel and serve in the same 13 capacity as Karen Hansen. And then, just a few days 14 ago, the person who was going to speak on her topic 15 phoned in ill. So, Barbara has very generously 16 agreed, right at the last minute, to provide us with 17 a presentation. 18 Barbara is currently a program officer at 19 the Fogarty International Center at NIH in the 20 Division of International Training and Research. She 21 manages international collaborative infectious disease 22 research training grants and international bioethics 275 1 training grants. Everybody who has a serious interest 2 in international research ethics hears from Barbara, 3 at least once a day. 4 (Laughter.) 5 DR. LEVINE: She manages the information 6 exchange that is truly worldwide. I say hears from 7 her every day, hears from her every hour. 8 (Laughter.) 9 DR. LEVINE: If that's an exaggeration, 10 correct me. Barbara, it's your program. 11 DR. SINA: Thank you. He's referring to 12 a list serve that I inherited just by accident and has 13 grown by leaps and bounds. And really, I just pass, 14 I just push buttons to pass information that I 15 receive. I'm very happy to do it and if anybody here 16 is interested in being on a list serve, please contact 17 me. It's very, it's a fun thing to do and easy. 18 I'm coming here to speak from the Fogarty 19 International Center, which is part of NIH, and our 20 primary mission is to support collaborative research 21 and research training between U.S. and developing 22 country scientists. What this means is that we are 276 1 always doing international stuff related to IRBs and 2 IRB training. And we have for a long time. 3 And just to set a base, all our programs, we have lots 4 of research we support that's both clinical or 5 epidemiology. We don't support clinical trials, so we 6 don't have that level of complexity or that level 7 budget, but we do support a lot of human subjects 8 related research and trainees conducting a lot of 9 research in their home countries. We require that all 10 these projects have IRB review both in the U.S. and in 11 the developing country, that all the faculty mentors 12 have human subjects education, just as we would for 13 the U.S. investigators, and that all the trainees have 14 responsible conduct of research training, either in 15 the U.S. institution or in their own country. And, 16 what this means is, over time, a lot of our grantees, 17 who are primarily U.S. people working in these 18 international sites, have had to put a lot of training 19 effort into setting up IRBs in these sites and setting 20 up training courses for their own grantees and 21 trainees. 22 So this is, you know, we were already 277 1 doing this before we started the program that I'm 2 going to talk about today. And there's been a lot of 3 -- and our grantees are very much devoted to this 4 effort. So that you can know that there's a baseline 5 happening out there that doesn't require a formal 6 training element that you're going see talked about 7 today, but this is happening. 8 Okay, just to go on, we have had this 9 program going where we have been training in 10 international bioethics since 2000, it was started 11 under Dr. Jerry Kirsch, and since that point, it's 12 grown quite large. And we decided that last year we 13 needed to look at what's happened over those five 14 years, and see if there was lessons learned, and 15 places we were missing, and where we should go next. 16 And, so that's where this talk comes from. 17 These are some of the topics I'm going to 18 cover, hopefully. I probably won't get through all of 19 it but I'm going to take it at least through the 20 training successes, so you can see where things have 21 been happening. 22 The goals of this program are diverse. 278 1 They're generally to provide in-depth research 2 bioethics expertise in developing countries, as a 3 means of strengthening the entire complex number of 4 ways that ethics enters the equation, both for the 5 researchers in the IRB setting and, hopefully, to 6 conduct local research and bioethical issues, and to 7 provide true homegrown expertise and leadership in 8 designing national and international guidelines to be 9 used in those countries. 10 So, these programs are supported to do 11 two things. Usually, they need support to develop 12 curriculum because, even in the U.S., there were very 13 few places that had a full set of curriculum ready to 14 go that focused on international research ethics. 15 And the other part, of course, is to train 16 people. And the training takes on two flavors. One 17 is the didactic in foundational courses of bioethics 18 and research ethics, going through both the 19 philosophical and the international guidelines and all 20 the things that you want to fill the background so 21 that the practice of it is drawn directly out of that 22 expertise. 279 1 And then, secondly, almost all our 2 programs provide practical experience as well. And 3 this involves sitting in on IRBs, the trainees design 4 their own courses to teach bioethics when they return 5 to their countries, conducting small research projects 6 in ethical issues of high importance to the trainees, 7 etcetera. 8 We have, one of the true goals of this 9 program, was that it would not be a U.S. based 10 training program. When we started, of course, that 11 was the easiest group of grantees to capture, but we 12 were very clear in our minds that we would try to 13 achieve at least 50 percent of the programs would be 14 located overseas. And we're at about two-thirds are 15 at overseas locations, at this point. So, in order to 16 accomplish that and actually have these grant 17 applications make it through the NIH peer review 18 system, even the U.S. applicants were, generally, 19 unfamiliar with submitting NIH grants. We required a 20 lot of sort of enhancing activities and offering of 21 planning grants in order to build a full training 22 program, both a curriculum and other training 280 1 activities. And we also provide a lot of grant 2 writing courses to help people submit these 3 applications. 4 I'm not going to go through the details of 5 all the present programs that are up and running, 6 there's 18 of them listed here, but I wanted to 7 provide these kind of details, just so you can see the 8 general characteristics of programs, because they're 9 very variable from place to place and from what 10 they're able to accomplish. 11 This is the first set of grantees that was 12 funded in the competition in the year 2000, so they've 13 had the most experience at this point. As you can 14 see, it was most easy to capture the American 15 applicants in this thing and we had three applications 16 that we supported as planning grants for the next two 17 years, so that they could come in with full planning 18 grants. All of them were successful in turning their 19 planning grants into full training programs. 20 The U.S. institutions tends to have fewer 21 trainees per year because of tuition costs, whereas 22 developing countries can really reach much further and 281 1 support more people. Many of the programs tended to 2 focus on regional recruitment of trainees as opposed - 3 - and some set it up where they were recruiting from 4 only their own country, such as India, I'll show you 5 in the next slide, but some also set it up that they 6 were working, their institution was already working 7 with several institutions overseas that they wanted to 8 develop this capacity and so they had channels sending 9 trainees from those particular countries. 10 And this is, the programs are added after 11 the 2002 competition, which greatly extended our 12 ability to work, or to have this program train people 13 from Asia. 14 And this was our last competition within 15 2004 and the bottom two are planning grants that are 16 re-competing, actually, in the batch of applications 17 that are sitting waiting to be reviewed in my desk 18 right now. So, we'll have another cohort going out 19 2006, maybe 2007. 20 One of the things we do with our programs 21 is to bring all the PIs annually to Bethesda and we 22 discuss a lot of training related issues, provide new 282 1 resources for these things. And OHRP has been 2 welcomed to attend these network meetings, I think, 3 since the beginning, and so were other of institutions 4 that are trying to build up capacity internationally 5 in research ethics, such as the Wellcome Trust come 6 regularly. 7 Finally, getting down to how we handled 8 the review, these are the panelists who reviewed the 9 program and, so far, David was there, so he can chime 10 in with any comments about, I leave things out. One 11 of the things we continue look at carefully concerning 12 our budget situation is where do we get funds for this 13 training. Another point we were very clear on at 14 Fogarty was that if this program was really going to 15 support the NIH, it needed to have buy-in from all the 16 different parts of NIH that do international research. 17 And so, we have all these partners and, you might see, 18 including NASA, who is doing human subjects research 19 in Russia, who have contributed funds to this training 20 and continue to contribute to the training overseas. 21 And we manage the program using their contributions. 22 So far and, again, this data is for the 283 1 first four years of the program, we've trained 167 2 people with Masters level intensive training. The 3 people you see in the short-term training were often, 4 and most probably were, IRB members who were doing 5 short courses related to these programs. 6 Just to, one of the, another goal is to 7 cover the world, so that any possible location 8 overseas would have an opportunity to do this kind of 9 training. We're not quite there yet but, regionally, 10 we did focus very highly on Africa, knowing that the 11 capacity there was at the lowest, probably the lowest 12 level. And the research needs were, especially 13 related to AIDS research at NIAID, were just 14 tremendous and the issues were also tremendous. So, 15 we have focused a lot and we've done quite well in 16 Anglophone, Africa and not so well in Francophone, 17 Africa and we have nothing happening in Luciphone, 18 Africa. So, we have a ways to go there. 19 We also needed to increase our effort in 20 the Middle East, and in Russian, and Eastern Europe. 21 So, the new RFA, the one we have applications for 22 right now, actually has preferences for people 284 1 developing programs for those three. 2 And again, most of our trainees, about a 3 third, have received Masters degrees but a lot of them 4 haven't and that's fine. Most of the people we are 5 capturing are already professionals who are coming for 6 this training. They really, many of them can't get 7 away from their current positions for more than a 8 short period of time to take this training. And also, 9 they were selected as being people in positions that 10 could have the most impact on changing their ethics 11 situation when they returned home. So, the 12 combination of things, we had to have a lot of 13 flexibility in the types of training available, degree 14 and non-degree, to make this work in the places we're 15 doing it. 16 All of the trainees have returned home. 17 It says 98 percent. One is working on a Ph.D., so I'm 18 not worried about that person returning home either. 19 These trainees, even though they're getting, actually, 20 quite short-term training compared to what we give our 21 other research trainees who are doing, you know, 22 working molecular biology and malaria and things like 285 1 that, have already contributed 80 publications to the 2 literature, which is a voice we really need to hear, 3 and I think they've contributed some very interesting 4 pieces to literature and in the meetings that they've 5 started to attend in larger numbers. It's great to 6 hear their voices. 7 Here are some specific training successes 8 I wanted to highlight to show you that people have 9 moved into prominent positions related to taking this 10 training. We had one trainee who went back and 11 immediately was sequestered by the government to set 12 up a national ethics review board in Nigeria and 13 received a presidential medal. 14 I guess the trainees starting a bioethics 15 at the Agricon University in Pakistan, I just visited 16 there a couple of weeks ago, where they supported the 17 global, we have a global forma on research and ethics 18 in developing countries that meets annually, and they 19 took this on and ran the whole thing, developed all 20 the cases. It was pretty impressive. And the 21 center's been supported by a Wellcome Trust actor, the 22 people, they were trained in our programs. 286 1 Some other trainee successes related to 2 IRBs, the trainee from Ecuador, whom immediately went 3 back and served as the consultant for their national 4 commission on bioethics. Again, people are acting 5 locally at their own institutions, but also are being 6 widely used as experts coming back to the United 7 States and running things at various meetings here. 8 So, they've really fed into all levels of activity 9 that are occurring in the world, at WHO, and they're 10 organizing things. And I feel like this is an 11 immediate contribution and with the people who most 12 need to be in there and saying what they need. 13 I'm not going to go into all the 14 recommendations from the panel, which I think you have 15 in your handouts. Basically, they were non-related to 16 IRB training, which I'm going to take as some kind of 17 stamp of approval that we're actually meeting those 18 goals in the appropriate way that the panel looked at 19 it. The one thing that I think we would like to do 20 better, and that is, is actually working better 21 amongst all of the organizations that are supporting 22 research, and NIH is a big one, in trying to match 287 1 these trainees to where they're needed most in terms 2 of the IRBs that are reviewing the most difficult 3 protocols, the places that need the most internal 4 training which these people are providing when they 5 are back at their own institutions. And that's a 6 really hard thing to set up, is to do this. And I 7 pretty much do it informally, at this point, by 8 requests from here and there but we would love to come 9 up with some mechanism to shape this in a more 10 effective sort of flow. 11 And, if anybody has any suggestions how to 12 do that kind of matching, I'd be glad to try and do 13 it. We are setting up a training tracking system to 14 keep track of all the trainees and where they are, so 15 we'll be able to provide, from that end, some 16 connection. 17 Thanks a lot. 18 DR. LEVINE: And thank you very much, 19 Barbara. Wonder what you -- it's impossible to 20 imagine what you'd have done if you'd had a whole week 21 to prepare. 22 (Laughter.) 288 1 I'll take comments or questions aimed at 2 clarification of Barbara's presentation. You were 3 perfectly clear, too. 4 And now let's open it for general 5 discussion. I would like it, if those who wanted to 6 make a comment or ask a question, would come to the 7 microphone, state your name, a brief of your location 8 when you're not here, and your comment. 9 I want to warn you that if you don't have 10 questions, I have a lot of them. 11 Yes, sir? 12 MEMBER GYI: Thank you for a very 13 enlightening presentation to everybody. Thank you for 14 helping us to really understand the issues and funding 15 mechanisms. 16 The question that I had with regard to 17 funding was more directed towards you, Dr. Lin. You 18 had a slide on there about payment for research ethics 19 training as a solution for one of the problems that 20 was listed. And I wondered what your thinking was 21 with respect to other funding agencies that would pay 22 for ethics training. Let me clarify where I'm going 289 1 with this. 2 You know, currently, even for IRB 3 services, I think that there isn't an appropriation 4 remuneration for IRB services in a line item for 5 investigators to pay for IRB services, because it's 6 bundled under some kind of an indirect cost recovery 7 system, I wondered if your solution addressed the 8 issue of payment for research ethics training as well 9 as supportive IRB related activities that has to 10 oversee investigator conductive research. 11 DR. LIN: I think what I was saying is 12 that if we can pull all the resources together and do 13 more of a systematic and global approach of not like 14 everybody, every different organization, is doing its 15 own, and if we can develop the, put the resources and 16 develop public and private organization partnership to 17 make it like a web video type of research. What I'm 18 talking about is the people, different organization, 19 devote or support budget for the more of systematic 20 training, rather than, like a little island, everybody 21 doing their own capacity building. I didn't mean for 22 IRB, cost for IRB review. 290 1 DR. LEVINE: Thanks. If you have a 2 comment or question, please just go to the microphone. 3 And if someone else has one, please line up behind her 4 and we'll get all the comments. 5 MS. MATHIAS: Hi. I'm Charlene Mathias 6 from the Division of AIDS. And, earlier in Dr. Lin's 7 presentation, she mentioned investigator training. 8 And I'd like to have Maureen Powers, perhaps, explain 9 how protocol registration works at the Division of 10 AIDS and how we have GCP training for our 11 investigators and how that is handled because I think 12 the committee needs to hear our approach. 13 DR. LEVINE: Maureen? 14 MS. POWER: Thanks, Shirley. 15 Yes, I think I should just point out that 16 I was asked to talk about IRB training but the charge 17 is actually looking at investigator training, too. 18 And, in fact, the Division AIDS, because it supports 19 so much research, both internationally and 20 domestically, provides a variety of training resources 21 and requirements, not unlike that that Dr. Saillot 22 described. We certainly have GCP training for our 291 1 institutions and all of our sites, all our key 2 personnel, are required to take human subjects 3 protections training. 4 MS. MATHIAS: Thank you. 5 DR. LEVINE: Thank you. David? 6 MR. BORASKY: Thanks. My name is David 7 Borasky, I'm with Family Health International in 8 Research Triangle Park. Family Health International 9 is a nonprofit organization that implements programs 10 and conducts research in the areas of public health, 11 mostly in low resource settings. And I'm a fellow 12 PHRP, but the good kind, like Bob, and Maureen, and 13 Karen. 14 (Laughter.) 15 MR. BORASKY: My question, I have just a 16 few sort of general questions for, I guess, both the 17 panel and maybe for SACHRP to think about, because, 18 obviously, SACHRP has to process the information from 19 these excellent presentations, and they're questions 20 that we face at FHI when we are planning to do 21 training in preparation for studies that we conduct. 22 So, my questions, and they're all pretty 292 1 short, but first of all, you know, who is the audience 2 that we're talking about for these studies? Is it 3 PIs, is it research staff, IRBs, is it the American 4 investigators, or Northern or Western investigators 5 that are going abroad to do studies in these places? 6 Is the goal to make Western or Northern bioethics 7 principles global? Because Bob talked a little bit 8 about that in his first presentation and, in fact, 9 that seems to be what a lot of the training is, to 10 some extent. 11 Related to that is the idea that, are we 12 trying to make people compliant with regulations or 13 are we trying to train them to be bioethics or in 14 areas of philosophical ethics? And I ask that because 15 a lot of what SACHRP is focused on, and a lot of what 16 our PHRP training is sort of focused on, is really 17 compliance with regulations. 18 And then, finally, is the goal of the 19 training that SACHRP is thinking about or considering 20 really to foster global expertise in bioethics, or is 21 it something different? 22 And I think that the answers to those 293 1 questions could be important because they will help 2 dictate programs, what programs like PHRP do, sort of 3 the who, what, when, where, and how of international 4 research ethics training. Thank you. 5 DR. LEVINE: Thank you. I would like to 6 ask Karen to begin the response to some of these 7 questions. 8 MS. HANSEN: I'd like to start out by 9 saying that I think it's all, it's somewhat like baby 10 steps, if you will. And, based on the experience that 11 I've had, we've, first of all, worked with 12 international sites and framed things possibly from a 13 U.S. foundation of regulation because, if they are 14 collaborating, they want to know and understand what 15 is expected and required and certainly be 16 understanding of those requirements. 17 But then, I think, the next step is to 18 then embrace, and we've done this through Barbara in 19 some of our, you know, on location programs, is 20 embrace the values of that culture and community and 21 that serves in the host country setting to, not only 22 nurture and support those in the host country 294 1 settings, for example, the Malawi conference, where we 2 have 12 countries represented, they're not just 3 hearing from a U.S. perspective, they get the 4 platform. We've had the comments from some that they 5 viewed the U.S. federal regulations as the floor. 6 They may go beyond that. And, on the flip side, we 7 hear the comment that you have these regulations, yet 8 we don't have regulations to empower us as an IRB or 9 as an ethic committee. 10 So, I think you start, in my experience, 11 you start with the floor, but then you embrace the 12 international community. And then, the next step is 13 bringing those international participants to the 14 United States and infuse that understanding in 15 conferences like PRIM&R or the case where we had the 16 IRB representatives at the Hutch. I invited the Gates 17 Foundation, PATH, Seattle Biomedical Research 18 Institute, University of Washington, all of the 19 investigators and sponsors that were conducting 20 research in Africa. And I asked them to come and meet 21 with the IRB reps of those countries visiting. And I 22 asked the IRB reps to share with them their view of 295 1 the research. 2 So, I think, in response to your question, 3 David, I think we start with what we know and then we 4 expand to gain our better understanding of what 5 knowledge they share with us. And then we also 6 embrace the cultural input and understanding to a 7 larger audience. And I think, for example, at the 8 PRIM&R conferences, I think the infusion of 9 international representation has certainly re-framed 10 and shaped the conversations in workshops, not just 11 the main lectures. We had a keynote speaker in 12 McKeesie (ph.), who was at a PRIM&R conference whom we 13 came to know, because Barbara, I believe, had 14 recommended him to speak and Dr. Levine, Bob. And so 15 I think it's just this mixture of infusion that is 16 going on and you start on the practical side of what 17 you know and then you embrace those who you are 18 involved with and work with them, as Bob put it, when 19 Maureen giving her talk, to really make everything 20 work collectively on a shared understanding level. 21 And I think, when I looked at the 22 conversations presented, or each of the presentations 296 1 and wrote my little comments down, what Bob had to 2 say, attitude. I think attitude shapes it all. And 3 I think it's so important. We've all had the 4 opportunity to visit international settings, not many 5 have. And I think when Melody says growth, it's not 6 the international setting growing, but we in the U.S. 7 setting, we need to grown in our understanding of what 8 the needs and views are from the other settings. 9 DR. LEVINE: Thank you, Karen. Let me say 10 that, when I wrote a note to the PRIM&R management 11 saying you've got to get McKeesie, I said, and if he 12 refused, kidnap him. 13 (Laughter.) 14 DR. LEVINE: He was very good. 15 I want to also pick up on a technical 16 point that David raised. Are we seeing ethics as 17 universal or are we seeing it as recognizing cultural 18 pluralism? I can't tell you what we are doing but I 19 can tell you and attitude of mine that's reflected in 20 the CIOMS document and, to the extent I've 21 participated in the UNAIDS and other documents in 22 there as well. 297 1 There is a debate among academic 2 philosophers that began around 2,500 years ago. And 3 the debate is whether ethics are universal or whether 4 ethics are, or whether there is some legitimacy to 5 cultural pluralism. 6 In classical Greek times, Aristotle was 7 able to say, ethics are universal. But then you had 8 to recognize the boundaries of his universe. Spartans 9 were barbarians and didn't count. Anyone who was not 10 a male gentleman citizen of Athens didn't count. So, 11 he was dealing with a relatively homogeneous universe. 12 I think there can be no doubt that ethics 13 is something, ethics are developed within particular 14 cultures, conversations that are directly connected to 15 the traditions and experiences, the history of the 16 culture. Ethical pluralism, cultural pluralism, is 17 not only acceptable, it's inevitable. We can't even 18 imagine what the ethical problems are outside of our 19 own culture until we go there and then we try to find 20 ways to deal with it. 21 Now, in recognition of this, the 22 successful international ethical codes do not aspire 298 1 to universalism. Nuremberg aspired to universalism 2 and nobody follows anything in that anymore. There's 3 other reasons for that as well. But there's a 4 recognition in, for example, the CIOMS document of the 5 legitimacy of cultural pluralism and what it aspires 6 to is a term that I call global applicability. That 7 means, as far as we know, this applies around the 8 world, today. But built into that is an assumption 9 that as we learn more, we're going to have to 10 continually revise and improve the standards. 11 Now, whose standards should prevail? I 12 don't know. It's awfully hard for people in the 13 United States to imagine that you would do something 14 anywhere in the universe without the informed consent 15 of the individual subjects. But that's not subscribed 16 to by everybody. The CIOMS document insists on 17 informed consent. But, as we know, and David as you 18 know, and some of the others who are experienced in 19 international work know, sometimes, there is sort of 20 lip service paid to these things. In Japan, I've been 21 informed by several people, that informed consent is 22 something we do to keep Americans happy, but they 299 1 don't believe in it, etcetera. I'm not going to give 2 all the examples. 3 So, we have big problems understanding. 4 It's going to take us years to understand the 5 situation well enough to begin to respond to David's 6 questions. 7 Yes, you're next, please. 8 MS. TOBIN: Mary Tobin, Impact, LLC. This 9 question sort of follows off of your statement. Is 10 there any situation in which it's unethical to train 11 researchers, international researchers, in bioethics 12 training, given that they'll then become more 13 competitive players in the world economy, if in fact 14 you know that that country that you're doing the 15 training in may not be a friend to the U.S. or to the 16 Western world? 17 DR. LEVINE: Maybe you could help us by 18 giving a concrete example? 19 MS. TOBIN: Okay. 20 DR. LEVINE: You want us to refrain from 21 going to North Korea, for example? 22 MS. TOBIN: Well, the example that I'm 300 1 thinking of is some training that I participated in in 2 Russia, basically training folks in IRB procedures. 3 And yet I know, and that was about three years ago, 4 and yet I know that there are still three or four 5 closed cities where research is going on and we don't 6 have access to that. And the research is biochemical. 7 Do we want to -- 8 DR. LEVINE: You feel like taking a crack 9 at that, Jean Louis? 10 (Laughter.) 11 DR. SAILLOT: Thanks, Bob. 12 (Laughter.) 13 DR. SAILLOT: I'm not sure I should have 14 to take a crack at it. The, you know, in terms of 15 the, first of all, biochemical, you know, I've been 16 trusted maybe in a bit more of the specifics, again, 17 I can talk from my experience, this is building a 18 capacity for the sake of having maybe a location that 19 would be more convenient. I'm not even sure as to 20 where the question, in terms of building capacity as 21 a potential convenience for the future. I was not 22 sure as to where you were coming in terms of your 301 1 question. 2 I know there are clinical research 3 activities that are performed in Russia. The 4 proportion of those sites is usually limited. There, 5 the way that it's implemented when such countries, or 6 Eastern Europe, or other countries throughout the 7 world, the standard that is being applied is, you 8 know, what I went through, or presented, in terms of 9 at least large forma, there's no difference in the way 10 that the research is being conducted. But, again, I 11 don't know that I'm answering your question. I'm not 12 sure exactly as to what your question is, actually. 13 MS. TOBIN: Well, for example, one of the 14 things that we found in Russia is that, given their 15 history, that researchers do not share information and 16 that the system was structured in such a way that 17 information was not shared. Nobody knew the whole of 18 what they were working on. And to follow up the 19 earlier statement about cultural values, they don't 20 change easily, neither do cultural systems, and, 21 therefore, we're not going to be moving into a system 22 where people necessarily have the free sharing of 302 1 information that we assume happens, and yet we're 2 going in and saying, in essence, we want to build 3 capacity so that you can take care of your own people, 4 but you can also compete in the global economy. I 5 mean, that's certainly one of the BTEP program, the 6 Bioterrorism Engagement Programs. 7 DR. LEVINE: All right. I'm beginning to 8 get closer to it. I don't think that everything in 9 human research in the United States is shared with 10 everybody. And, David, aren't there some components 11 of clinical investigations that FDA maintains as 12 secret or proprietary information? 13 MEMBER LEPAY: There are certainly levels 14 of information that do constitute proprietary 15 information that can't be disclosed by government 16 officials. Certainly sponsors of companies, sponsors 17 of the studies, have the ability to do that in their 18 own discretion. 19 MS. TOBIN: Okay. Thank you. 20 DR. LEVINE: So, you don't have to go to 21 Russia to find those problems. 22 MEMBER BARRATT: Also, classified human 303 1 subjects research. 2 MEMBER LEPAY: There is classified 3 research as well. 4 MS. TOBIN: Thank you. 5 DR. LEVINE: Did everyone get that? When 6 research is being sponsored by the intelligence 7 community, very often the details of such things is, 8 the purpose of the research, are not known to IRB 9 members, unless the IRB, all members happen to have 10 the appropriate level of security clearance. 11 Yes, please? 12 MEMBER JONES: It's going to change the 13 topic. Good for me. 14 But, so, we've talked around this, but 15 and, you know, all the wonderful things that are being 16 done, could we say, these are the stars. But it goes 17 back to one of the questions that was asked to frame 18 this session is, whose obligation is it to train and 19 to provide the resources? And, you know, beyond, a 20 lot of the focus was, even with GCP and training IRBs, 21 are at the process where maybe the research has 22 already been formulated, rather than an actual design, 304 1 implementing ethics on the design. 2 So, really, two questions then. The first 3 is, that, again, whose obligation is it, how are we 4 going to, like Melody said, get a systematic across 5 the board, just not an isolated process -- what could 6 we designed that would make it, you know, 7 comprehensive, like to answer her question. But then, 8 the second question, that Bern Schwetz talked about, 9 where when we look at the big world and where is the 10 implicit risks to ethics. And highlighted in that is 11 that box between the PI and the subject himself. And 12 so the kinds of training that you're doing, how is it 13 impacting that box? What are the issues 14 internationally that are different in that box between 15 the PI and the subject that should be addressed by 16 training that maybe aren't yet? 17 DR. LEVINE: The box you refer to is 18 almost a complete unknown in the United States. And 19 we don't know any more about it outside the U.S. 20 I want to turn, though, to your first 21 component of your question. Whose obligation is it to 22 provide training to the people of the world? And I'm 305 1 going to ask Barbara. 2 DR. SINA: Well, I don't, I guess I don't 3 segregate ethics training away from training how to 4 become a researcher, training how to become and IRB 5 member, training how to be a participant in any part 6 of this enterprise. I think it's everybody's 7 responsibility to train themselves and provide 8 training to others, as much as you can. I mean, I 9 think it's generally my opinion that it's been put 10 into this other category and that's why it is not 11 imbued in every part of what we do, because it's an 12 add-on. It's a special thing we do on top of 13 research, as opposed to it's part of research, it's 14 every way involved in research and you are always 15 doing it and are always involved in ethical, just by 16 example. 17 DR. LEVINE: Barbara, I agree with 18 everything that you've said. However, Fogarty puts a 19 lot of its resources into sending people around the 20 world to train people in bioethics. They don't send 21 out anyone to train people in biostatistics or -- 22 DR. SINA: Yes, they do. 306 1 DR. LEVINE: -- pharmacology. Oh, you do? 2 (Laughter.) 3 DR. SINA: We have 27 different programs. 4 So -- 5 DR. LEVINE: You're doing that? 6 DR. SINA: Yes. 7 DR. LEVINE: Well, I'm glad. You didn't 8 train me on that. 9 (Laughter.) 10 DR. SINA: You didn't send us an 11 application. 12 DR. LEVINE: And what about pharmacology? 13 DR. SINA: Yes. I mean, -- 14 DR. LEVINE: You do that? 15 DR. SINA: Yes. 16 DR. LEVINE: Wonderful. All right. So, 17 there you are. But is it a -- 18 MEMBER JONES: But still, you know, that's 19 -- I mean, that's not completely answering the 20 question. 21 DR. LEVINE: No. 22 MEMBER JONES: I mean, the resources, I 307 1 mean, and I agree with the premise, but we still have 2 a gap. Or maybe my perception is wrong, there is no 3 gap. You know, but maybe you should comment on 4 whether or not there is or isn't. 5 DR. SINA: Well, there's definitely more 6 work to do. And there's definitely more resources 7 that could be used to very effectively do what we're 8 doing now in a wider sphere, and to do more. I think 9 that's clear. But I hesitate to put the 10 responsibility into one little box because I think if 11 everybody took responsibility, the resources and the 12 energy to get this done would happen. 13 DR. LEVINE: I think another piece of it 14 is that if it's terms of obligation, I don't think 15 there's an obligation to go out and teach bioethics, 16 or research compliance, or anything like that, to the 17 world. I think there is an obligation to see to it 18 that, when American funds are being spent, that 19 they're being conducted in accord with what we would 20 consider ethically acceptable procedures. Whether or 21 not this means, in David's words, that we have to 22 export the entire American regulatory corpus, that's 308 1 the subject of some debate. But I think that it's not 2 the general obligation to go out there and teach 3 ethics, but more an obligation to see to it. 4 Well, if NIH wants to give any money for 5 people to do research in low resource countries, then 6 it's got to make the investment to meet the other 7 obligation that I mentioned. I hope that is 8 responsive. 9 And, Melody? 10 DR. LIN: I, personally, think that those 11 who fund a research either by U.S. government or by 12 U.S. pharmaceutical industry have a best interest to 13 make sure that the research ethics training, including 14 researcher, ethics committee, and the staff that would 15 be the interest for them because of, after all, you 16 are using those data, you wanted to be sure of the 17 result of the research is a good quality. And that 18 benefit to the sponsor and it benefit to those who 19 fund the research. 20 DR. LEVINE: Yes, sir? 21 MEMBER POWELL: It is sufficient to simply 22 know that someone's gone through the ethics training 309 1 to be an investigator, or what would you require to be 2 able to determine whether an investigator has a 3 sufficient understanding of ethics to be able to do 4 different types of research? 5 DR. LEVINE: I'm going to go to Maureen on 6 that one. You're afraid of that one. 7 MS. POWER: You know, I think it's really 8 very difficult, in this and in many other areas, to 9 sort of test competencies. I think that, in many 10 areas, we rely on the fact that training has been 11 provided to and that information has been conveyed 12 and, hopefully, assumed and that will effect an 13 appropriate change in behavior. I think, in the 14 reality, we understand that it's a much more 15 complicated situation than that. 16 I think that we also know that there are 17 a number of checks and balances built into the systems 18 in order to ensure that, to the extent possible, that 19 investigators are behaving appropriately, that their 20 staff are behaving appropriately, that IRBs are 21 deliberating effectively. So, we don't have, at 22 NIAID, we don't have core competencies that we test 310 1 people on. You know, we look at the credentials and 2 the experience and the qualifications of the 3 investigators. 4 DR. LEVINE: I don't know if you feel you 5 got an answer to your question, but we will never know 6 for sure what's actually being done when the 7 researcher and the subject are alone together or, for 8 that matter, when the doctor and the patient are alone 9 together. You don't have to look to ethics to find 10 examples of this. 11 For example, you may recall, some years 12 ago, that when they licensed Clozapine for treatment 13 of people with schizophrenia, one of the anxieties was 14 that, in the clinical trials, they found a one percent 15 incidence of agranular cytosis and they could head it 16 off, if they detected the lowering white count in 17 time. So, the corporation put it out with a 18 requirement that you could not prescribe this drug 19 unless you availed yourself of the services of a 20 corporation, not their own corporation, to check white 21 counts on the patients. 22 Well, the psychiatrists of the U.S. got up 311 1 in arms. They said, we know how to draw blood for a 2 white count. And they said, but in the clinical 3 trials where we paid people to draw blood for a white 4 count, the compliance rate was about 80 percent. That 5 means 20 percent of your people are exposed. And we 6 expect that the compliance in practice would be less 7 than that. So, even something as simple and 8 mechanical as drawing blood -- was it 80 percent? 9 Right around. 10 So, you know, it's a lot easier to draw 11 blood than to give a careful explanation of the right 12 to withdraw without loss of benefits. We're always 13 going to have that problem. The people who are really 14 sitting ducks are editors of journals. All they know 15 is what the investigators wrote in there. They don't 16 know if they did any experiments. 17 Yes, please? 18 MS. EHLER: I just want to make a comment 19 and it's not a question. I was fortunate enough to 20 join Maureen and Karen when they conducted one of the 21 PRHP sessions in Durban this past fall. And, as 22 somebody who applies OHRP regulations to the Division 312 1 of AIDS studies, it was very enlightening for me to 2 attend and to hear the perspectives of the 3 participants in the workshops because it's very easy 4 for us, here in the U.S., to be part of the research 5 enterprise and to apply the U.S. regulations. But, if 6 you don't know the feelings of the people that are 7 actually participating in the research, I think it's 8 really important for us to have their perspective and 9 try to, perhaps, apply this when we're trying to apply 10 the U.S. regulations to studies that we conduct. 11 Anyway, it was a wonderful, wonderful 12 experience and I would encourage anyone who has the 13 opportunity to go abroad and to talk with IRB 14 administrators and members to do so, because it was a 15 great experience. Thank you. 16 DR. LEVINE: Thank you. Bern? 17 SECRETARY SCHWETZ: I'd like to revisit 18 the question of what capacity building means in the 19 context of Nancy's comment, are we at the mark or not? 20 Capacity could be built either on demand 21 or it can be built independent of demand. And I'm 22 assuming that we're doing some of each but, primarily, 313 1 we're building it on demand. 2 Knowing that there is a significant 3 increase in the amount of research being done outside 4 the U.S. that's funded by various U.S. institutions, 5 private and non-private, will we be able to continue 6 to meet the needs by demand kinds of training or is it 7 possible that we'll reach some point in this curve of 8 the amount of research being done outside the U.S. and 9 we can no longer meet the needs by simply going there 10 two months, six months before the medical team arrives 11 to do the experiment, or the surveyors arrive to do 12 their experiment? At that point, it would seem as 13 though we're in trouble, if we haven't built the 14 capacity to build the capacity and we're doing it only 15 on demand, one study at a time. 16 DR. LEVINE: Bern, what you've done is 17 zeroed in on one of the most vexatious and refractory 18 problems in international research ethics. It's one 19 of those problems that CIOMS responded to with a 20 procedural response, that there should be, at the 21 outset of research, what it calls a community 22 engagement, where people reach an agreement on 314 1 scientific design issues, on what is adequate by way 2 of capacity building, what is adequate in terms of 3 reasonable availability of the product in case it 4 proves successful. All of these are turned over to a 5 procedural fix because nobody could specify any 6 algorithm for how to decide in particular cases. 7 The assumption that's implicit in there is 8 that different types of programs will call for 9 different levels of capacity building. If you're 10 moving into a country with a full-scale vaccine 11 development program that's likely to last seven to ten 12 years and involve 30,000 subjects, your obligation to 13 build capacity is very much greater than it is if all 14 you're doing is a simple check of a community to check 15 out the prevalence of bedbugs, which is an activity 16 that was carried out in Africa at one point, on one 17 occasion. 18 So, these are things that we hope we've 19 put the procedures in place to reach solutions that 20 would be satisfactory to all concerned. 21 DR. SINA: I think our programs and the 22 decision we made at the beginning was not to focus on 315 1 short-term training, but to provide the deep expertise 2 where people would walk away and become the experts in 3 their countries. They would serve where people would 4 go to them to become trained. They would serve as the 5 person to provide guidance to the IRBs, to the 6 national commissions on ethics. 7 So, I think that this is the long term, 8 sustainable expertise that will be in the countries 9 for whoever is going to do research in those 10 countries. The people themselves in those countries 11 or collaboration from outside. 12 So, it takes longer, it's not on demand. 13 Sometimes it looks like we're not training the right 14 people for it to match the exact research needs of 15 NIH, at that moment, but I think, over the long run, 16 it's a stronger system. 17 DR. SAILLOT: Let me react. As we were 18 talking, I think when Melody was talking about, you 19 know, what the role is for the sponsor, for example, 20 and going back on demand, one of the challenges, I 21 don't have the answer, but I think if we talk about it 22 we may be able collectively to have a better answer to 316 1 address what I'm going to highlight, is that, by 2 design, the studies conducted by sponsors, 3 pharmaceutical sponsors, are really targeted for a 4 period of time, you know, at a study. And then once 5 the study is over, you know, the same sponsor may or 6 may never come back to the same sites. Although, you 7 know, if there is an investment in a therapy area, in 8 a disease area, you know, there's that building for 9 the longer term, but by default, it is more of the one 10 time event than it is building long-term capacity. 11 That's one of the challenges for industry 12 participation. 13 The other, and actually I had the 14 discussion in a completely different topic about 15 monitoring and the way that monitors and audits are 16 being made between the industry and NIH, where NIH 17 always function, well, NIH or National Cancer 18 Institute, function with the same institutions over 19 and over and over again. So, it's easier to be able 20 to provide a more, a long-term strategic investment 21 into the capacity building, as it is for the sponsor. 22 It is very difficult, right now, what I described, is 317 1 very study-centric, center-centric, so there may be 2 some thoughts. I mean, there's some participation in, 3 you know, the either the institution overhead or some 4 of the funding that are embedded into the support that 5 the sponsors are providing that could be invested by 6 the institutions in a longer term way, but it would 7 actually require a significant paradigm change to be 8 able to -- 9 And I think Melody's right, the industry, and I 10 think I made the same comment at the building of 11 capacity for central IRBs, the industry will be 12 willing to invest if it knows that, you know, it's 13 helping and adding sites that are more reliable, that 14 will provide, you know, appropriate training, the 15 level of risk would be lower. There is some level 16 risk because aversion, you know, that can provide a 17 better level of comfort of sponsors. And I think that 18 folks would be willing to participate, but there's not 19 really a mechanism to do that, at least that I know 20 of. 21 And going back to the globalization, there 22 may be some thoughts that are being put into that. I 318 1 don't have the answer to that, but I wanted to put 2 this on the table. 3 DR. LEVINE: Bern? 4 SECRETARY SCHWETZ: I want to find out if 5 the two systems are helping each other or if they're 6 independent. Because it would seem as though the 7 long-term system should help you, Jean Louis, if you 8 arrive some time and find that people who have been 9 trained, and I can just add to it. Or, that you, 10 Barbara, find out that gee, there were two companies 11 who did studies in this country and they trained a 12 whole bunch of people, so now I've got a head start in 13 providing training. It's of a long-term nature. And 14 if these two could be designed so that they help each 15 other, we'd be further ahead. 16 DR. LEVINE: Very good point. Maureen? 17 MS. POWER: Well, I just wanted to 18 comment. To a very large extent, we've, within the 19 NIH community, we have utilized that model. I mean, 20 Barbara and I have worked very closely together. 21 She's clearly invested in the long-term. And we're 22 clearly interested in the long-term, but trying to, 319 1 you know, shore things up and provide fundamentals in 2 the short-term. And it's been very effective for us 3 to collaborate and to utilize, as I mentioned briefly, 4 to utilize trainees that have emanated from these 5 programs as speakers. And I think it provides them 6 with a credibility that they need to have and the 7 visibility that they need within their own 8 institutions to be able to, and within their own 9 countries, to take a larger leadership role. So, I 10 think we already are trying to accomplish that. 11 The larger things is to sometimes involve 12 many other partners. Just one is sort of, for the 13 training that we have done, I think I would say is 14 that the NIAID has vis-a-vis the institutional review 15 board training, has always reached out to experts and 16 tried to forge partnerships. And so, we've always 17 included Fogarty, PRIM&R, experts here in this room, 18 involved in the training activities, as a way of -- 19 and we've also collaborated some of the nonprofit 20 foundations that are doing research in the regions as 21 well. 22 DR. LEVINE: Karen, you're next and then 320 1 David. 2 MS. HOFFMAN: Hi. I'm Karen Hoffman. I 3 work at the Fogarty Center in the policy office. I 4 just wanted to respond to Dr. Schwetz with respect to 5 the question about are we getting to the mark, in 6 terms of capacity building. And I think that we're 7 beginning to see some glimmers of that. I can just 8 attest to the fact that both Barbara's comment about 9 being in Karachi and Pakistan and also at the 10 University of KwaZulu-Natal, I think that there are 11 several countries around the world that are beginning 12 to acknowledge their own role in helping to develop 13 the capacity in these places. 14 And, for example, at the University of 15 KwaZulu-Natal, there is now a group of about 30, 3-0, 16 people who constitute lawyers, philosophers, 17 psychologists, researchers, medical doctors, and 18 community, who now form the core of a bioethics group 19 just in one center in South Africa, many of whom have 20 been supported by many institutes of the NIH, 21 predominantly NIAID, but also the Fogarty Center, not 22 just for bioethics, but for other areas. And I think 321 1 that these people constitute a very important group, 2 just within South Africa, as well as others at 3 different centers. 4 So, I think, in answer to your question, 5 I think, as I said, there are countries that are now 6 seeing the need for this themselves. And I think 7 that's the best sign for us all, that there is a 8 willingness to collaborate and a willingness to 9 acknowledge that high standards are needed in order to 10 do so. 11 DR. LEVINE: Thank you very much, Karen. 12 You picked out one example but Fogarty has also been 13 instrumental in developing ongoing relationships with 14 places like St. Petersburg in Russia with Pretoria, 15 and I could go on. There's quite an impressive list 16 you're building. And this develops a momentum of its 17 own, where they're beginning a beginning. They are 18 taking responsibility for the continuation. 19 David? 20 MEMBER LEPAY: I was just going to add, in 21 somewhat, I think, in answer to Bern's question. I 22 think that we are, you know, certainly, I think we 322 1 have to talk about looking at both the short-term 2 project oriented education and training and, of 3 course, from FDA, I think we've used our inspection 4 program largely as a trigger for, in fact, moving that 5 with industry over a period of time in the development 6 of standards. 7 I think where we're going on the longer 8 term, though, is the strategic and that we see the 9 long-term approach that we should be taking is that of 10 trying to develop other regulatory authorities and 11 putting our efforts, our capacity building efforts in 12 that direction because, again, they have the legal 13 jurisdiction within their own country. If we can 14 train them, in fact, to be able to education within 15 their own country, we think that that may be the most 16 appropriate leveraging. And working with 17 organizations now, such as WHO, which has taken up 18 much of this same sort of philosophy in the GCP arena, 19 and again, not in a prescriptive fashion. I think, 20 you know, I keep alluding to WHO's handbook for 21 implementation that's going to come out in the GCP 22 area in the next couple of months, I think it does 323 1 embrace some of the thinking that we're trying to take 2 to the future of GCP education. While it's built on 3 documents such as ICH and CIOMS, the approach was 4 taken a bit differently and that is, it built off of 5 a higher level of GCP thinking. That is, off of the 6 fundamental principles of GCP, instead of the 7 particulars of specific individual standards and 8 individual tasks that have to be done and then try to 9 build back to how you put tasks back together in a 10 framework of those principles, where those principles 11 come from, how they derive not just from industry 12 government related documents but from ethical 13 documents and otherwise. 14 So, I mean, I think you have to have both 15 levels of strategy. 16 DR. LEVINE: Thank you. Ernie? 17 CHAIR PRENTICE: First of all, I'd like to 18 thank the panel for some very interesting and 19 informative presentations. Secondly, I would like to 20 convey the apologies of some of our SACHRP members who 21 have planes to catch. Plus, there was a complicating 22 factor, there was an automobile wreck, apparently, on 324 1 the road to the airport, which tied up traffic. So, 2 some of our individuals who had a little bit earlier 3 flight, so, you know, we're going to have to try to 4 get there in time, otherwise, they would have missed 5 their flight. So, I'm sure they wish they could have 6 been here. 7 You know, I've been, I'm actually 8 fascinated by the initiatives that you've described to 9 provide research ethics training internationally. I'm 10 not that familiar with the status of international 11 ethics training. I know a little bit about Singapore 12 and Taiwan. I know far less about all of the other 13 areas. But it's very clear that these are really 14 substantive programs that you're presenting and the 15 idea of training a core group of people who, in turn, 16 can launch initiatives in the country is, obviously, 17 the way to go. 18 So, that's the premise for my question. 19 In looking at the evolution of research ethics 20 training in this country, which has been pushed along 21 by a few bumps in a road, like some tragedies, some 22 shutdowns, etcetera, and we've seen a rapid increase 325 1 in the need to provide ethics training in the U.S., 2 particularly since probably 1998, and, as a matter of 3 fact, NIH never even had a requirement until 2001 and 4 then CITI under Karen and Paul's leadership, have 5 launched a training program that deals with aspects of 6 research ethics. At the same time, however, we've 7 seen a migration of clinical trials out into the 8 private sector and it's estimated that somewhere 9 around 70 to 75 percent of all clinical research is 10 conducted by private practice physicians in local 11 settings where, other than maybe what a pharmaceutical 12 company require in terms of investigator meetings, 13 there is no ethics training requirements whatsoever. 14 So, I see a little bit of a disparity 15 going on here where, in the U.S., we've got 16 universities who have launched fairly significant and 17 substantial training programs for their investigators, 18 and we have private practice physicians who have 19 absolutely no training whatsoever, and then we're 20 launching these efforts overseas to provide really in- 21 depth training for investigators overseas, which seems 22 to me that we're not even doing some of that in our 326 1 own country. So, I'm just kind of curious as what you 2 think about that. 3 DR. LEVINE: Barbara? 4 DR. SINA: I don't know all the 5 initiatives at the NIH, but there's certainly several 6 training clinical researchers that all include ethics 7 training. So, that's, just that piece of it, I think 8 is being covered. 9 As far as the private practice folks, you 10 know, I'm coming from being a faculty member at a 11 university and where I saw the real enthusiasm for 12 delving into the ethical issues was at the 13 undergraduate level. I mean, the kids just grabbed 14 onto this stuff, and loved struggling with it, and 15 loved having these discussions related to whatever was 16 in the news or whatever topic you wanted to bring 17 before them, and, in my mind, that's where we aren't 18 doing almost anything which would reach. I mean, if 19 you started talking about research ethics to every kid 20 who was getting a biology degree, who went to medical 21 school and became your private practice physicians, at 22 least they'd have a base to live on. Plus, people 327 1 learning how to be researchers, are choosing a 2 research career, this would automatically in their 3 head as part of their training from time zero. So, I 4 see that that's a piece that we haven't approached at 5 all and, again, would imbued a whole enterprise. 6 Everybody would at least have some exposure. It 7 wouldn't be the in-depth, it wouldn't be directed 8 towards conducting a clinical trial, but there would 9 be a base. 10 And that's just a personal opinion. It's 11 not behalf of the NIH or Fogarty, but I just have this 12 feeling that would be a place to start. 13 CHAIR PRENTICE: And I agree with you. 14 So, what we're saying is we're not reaching all the 15 investigators in the U.S. Are we doing a better jobs 16 overseas in training investigators? 17 DR. LEVINE: Barbara? 18 DR. SINA: You know, as I -- you saw the 19 numbers that we've trained so far. That's not nearly 20 enough. We need to do a lot more. 21 CHAIR PRENTICE: So, if you had to talk 22 about percentages, where are you? 328 1 MEMBER JONES: Were those investigators? 2 DR. SINA: Most of the researchers, yes. 3 CHAIR PRENTICE: Where are you in terms of 4 percent? 5 DR. SINA: Percent? I don't know. 6 CHAIR PRENTICE: Just a rough -- 7 DR. SINA: I have no idea of the number of 8 international investigators that are out there. 9 CHAIR PRENTICE: But I assume it will be 10 a very small percentage, at this particular stage. 11 DR. LEVINE: I would say slightly under 12 100th of one percent. 13 CHAIR PRENTICE: Okay. That's what I 14 thought. 15 I want to go back to a question that David 16 asked and it was their last question. And it was not 17 answered. And it's probably good that it was not 18 answered. And that was relative to SACHRP. You 19 asked, what is SACHRP going to do with all of this? 20 If you look at our charter, we are charged 21 with advising the Secretary on all aspects of human 22 subject protection, including international studies 329 1 and populations. We had a panel, as was indicated 2 earlier by Melody, and you were on that panel, where 3 this was our first consideration of the issues. And 4 that was back in 2003 and now we're back in 2005, or 5 we're forward to 2005, we're looking at this again. 6 Okay? And what we try to do when we have these 7 panels, we try to identify the issues. And then we 8 try to determine, is there a role for SACHRP, in terms 9 of providing advice, providing recommendations, 10 launching initiatives. That's what we try to do when 11 we have these panels. 12 So, I guess I'm going to take your 13 question, okay, and I'm going to ask the panel to tell 14 us what they think SACHRP might do to help resolve 15 some of the issues you've identified and the goals 16 that you have. 17 MS. HANSEN: I guess one of things I see, 18 since we mainly heard from funding agencies, and 19 regulators, and FDA, and so on, and sponsors, is that 20 if you are from an academic center and you are doing 21 your first time work with international settings, 22 where can good resources be located for an academic 330 1 center who is now collaborating, we just learned one 2 of their investigators wants to work in an 3 international site, how can we best identify training 4 opportunities and resources, does Fogarty have a 5 scholar there, is there an IRB there, check the FWA 6 site to determine if there's another IRB that can 7 start working there that's been in existence. But I 8 think, from the academic or medical institution 9 perspective, that would be really helpful to have 10 those resources made available. We've all come to 11 know each other at the table as collective resources 12 for each other. But I am very concerned about the 13 centers who may not have had that experience yet and 14 they need to know where to start, and who to work 15 with, and who they can count on for providing training 16 or using as a resource for training. I think that 17 would be very beneficial to academic centers holding 18 FWAs within the U.S. And then, likewise, it will 19 shift on out there to those having the FWAs outside of 20 the United States. 21 CHAIR PRENTICE: Okay. Melody? 22 DR. LIN: You want a suggestion, right? 331 1 Or recommendation? 2 CHAIR PRENTICE: You can characterize it 3 any way you want. 4 DR. LIN: Okay. I would suggest that 5 SACHRP endorse or embrace the OHRP concept for the 6 partnership of public and of private organization to 7 do the -- to identify core curriculum, standardized 8 curriculum, and blend with and flexible for 9 incorporating local customized content for more 10 systematic training for the distance learning, using 11 the distance learning technique. 12 CHAIR PRENTICE: You're saying using the 13 internet? 14 DR. LIN: Yes. And then, first of all, 15 you need to identify what's the available resources as 16 a standard curriculum and then you allow the local 17 customized context. And then, then it can be used 18 anywhere, anytime, for either individual or group. 19 CHAIR PRENTICE: I assume that that's 20 something that OHRP has discussed as initiative that 21 might be possible at some point in the future? 22 DR. LIN: I would -- we got this concept 332 1 from, actually, the third recommendation of the first 2 international panel and then we sort of discuss in- 3 house. 4 CHAIR PRENTICE: Okay. I guess we have to 5 go in line, David, because I started with Karen. 6 MEMBER LEPAY: I think I'm going to defer 7 comment for the moment, I think. 8 DR. LEVINE: May I ask what time we're 9 going to adjourn? 10 CHAIR PRENTICE: Well, I don't know if the 11 car wreck has been taken care of yet -- 12 DR. LEVINE: Yes, I've got to -- 13 CHAIR PRENTICE: We're supposed to adjourn 14 at 4:30, sometimes we go a little bit over. 15 DR. LEVINE: All right. It's just that I 16 also have an airplane that might be a tight fit. I 17 have a 6:30 flight. 18 CHAIR PRENTICE: A 6:30 flight? It's -- 19 how about we try to wrap this up in another seven 20 minutes? 21 DR. LEVINE: Good. Maureen? Tell him 22 what to do. 333 1 (Laughter.) 2 DR. LEVINE: In one quarter of seven 3 minutes. 4 MS. POWER: Okay. So, somewhat following 5 along the same lines that Melody was discussing is, I 6 actually think that the availability of a core 7 curriculum that could in fact be utilized by people 8 here in the United States that want to do training 9 overseas or by, more importantly, institutions, you 10 know, foreign institutions, I think, so that they 11 could do sort of their own training and develop their 12 own programs, I think would be extremely helpful. 13 And that while I think that the internet 14 is a wonderful tool to utilize, it's not always the 15 best way for people to learn, in some situations. So, 16 I think other modalities that could be used in face- 17 to-face meetings, I think, would be extremely helpful. 18 So, I think that just making availability of materials 19 to sites so that they could adopt them themselves. 20 And I guess I would look at it as a larger 21 picture and I would say not just looking at training 22 local investigators, or training the IRB, but looking 334 1 at it from the broad perspective of an institution 2 developing a human subjects protections program, and 3 what all of the steps are, and what all it is that 4 they need to do, and how they can put all of that 5 together so that they have a full fledge. Because 6 we've talked about training, but there's many other 7 components about developing websites and communicating 8 with their institutional investigators, and 9 communicating with outsiders, and there's a whole lot 10 that goes into that. 11 CHAIR PRENTICE: Okay. Thank you. 12 DR. SINA: I'm not as familiar with SACHRP 13 as the other people in the room, so I may be a bit 14 naive about what's possible. 15 I think that advocacy role that you've 16 shown, just in having this topic as, in this fora, is 17 great because it sends the message that this is a 18 capacity that we think is important and that we see as 19 essential to the research enterprise and, you know, 20 and that comes back to all of us at our various 21 locations that we should, both in the long-term and in 22 the short-term, really put effort and energy and 335 1 resources into this enterprise, to make it a better 2 place. 3 DR. SAILLOT: I don't know that I have a 4 recommendation for SACHRP. I definitely, I mean, 5 applaud getting these discussions and these panels 6 together. It's at least airing the issues. 7 In terms of from the sponsor's 8 perspective, as I mentioned, it is the issue of long- 9 term capacity building, I don't see an easy 10 recommendation or a simple recommendation to address 11 these thoughts that I know there's quite a bit of 12 discussion around, you know, PhRMA and other 13 association, you know, the PPIs is a good one as well, 14 in terms of certification of investigators, for 15 example, where you have a minimum curriculum that 16 could be valuable that may also address your question 17 around the private practice. We talked about having 18 the curriculum of clinical research, including ethics, 19 as part of the regular medical curriculum. 20 You know, and that has not much to do with 21 industry but maybe private-public partnership in terms 22 of foundation monies that, you know, that may be a way 336 1 that is a fund that is made available which is not 2 specifically related to a research program so that 3 conflict of interest may not be, you know, may not be 4 an issue. 5 I guess that we need to continue giving it 6 some thoughts. 7 DR. LEVINE: We skipped you? 8 MEMBER LEPAY: No, that's fine. I really 9 don't have anything to add. 10 DR. LEVINE: David has nothing to add? 11 CHAIR PRENTICE: You have the last word. 12 DR. LEVINE: I would suggest that we 13 really can't come up with anything that's going to be 14 new and useful on the spur of the moment here. I 15 think what you have seen, though, is that there are 16 some people who are doing things that appear to work. 17 And I would try to collect these people in some sort 18 of a subcommittee and give them some time to share 19 what, you know, you said that I'm good at keeping 20 people to their time limit. When you do that, though, 21 you cut off a lot of good stuff. We didn't see all of 22 Barbara's slides and we didn't see all of Maureen's 337 1 slides, and so on. But I would take people like 2 Barbara and Maureen, some of the others, Karen, David, 3 people who have had success, Karen Hansen and Karen 4 Hoffman, people who have had success doing this, and 5 I can't name everyone in the room who is doing this, 6 and put them together on a sort of a task force and 7 ask them to come up with a program. 8 I would suggest that, even though some of 9 my colleagues have emphasized the importance of a core 10 curriculum, that a core curriculum without personal 11 involvement of dedicated teachers is not going to 12 work. You've got to have people who are dedicated, 13 like some of the people you've heard from this 14 afternoon, who not only are dedicated to making the 15 program function, keeping people on time, and so 16 forth, but are dedicated to getting in there, sitting 17 with people from other parts of the world, and 18 exchanging in the spirit of sharing amongst equals. 19 Having said that, I want to say thank you, 20 once again, for allowing me to participate in this. 21 And thank you to all the panelists for your splendid 22 offerings. Thank you. 338 1 (Applause.) 2 CHAIR PRENTICE: I think it's evident that 3 we've closed. 4 (Laughter.) 5 CHAIR PRENTICE: Okay. Thank you 6 everybody. 7 (Whereupon, at 4:44 p.m., the foregoing 8 meeting was adjourned.) 9 10 11 12 13 14 15 16 17 18 19 20 21 22