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