1 DEPARTMENT OF HEALTH AND HUMAN SERVICES SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION MEETING MONDAY NOVEMBER 1, 2005 The Advisory Committee met in the Jefferson Ballroom in the Radisson Hotel Old Town Alexandria, 901 North Fairfax Street, Alexandria, Virginia, at 8:30 a.m., Ernest Prentice, Ph.D., Chairman, presiding. MEMBERS PRESENT ERNEST D. PRENTICE, Ph.D., Chair BERNARD A SCHWETZ, D.V.M, Ph.D., Executive Secretary CATHERINE SLATINSHEK, M.A., Executive Director THOMAS L. ADAMS, CAE CELIA B. FISHER, Ph.D. NANCY L. JONES, Ph.D. FELIX A. KHIN-MUANG-GYI, Pharm. D. SUSAN KORNETSKY, M.P.H. JAMES H. POWELL, M.D. ADA SUE SELWITZ, M.A. SUSAN L. WEINER, Ph.D. Ex Officio Members PEG BARRATT, Ph.D., National Science Foundation HOWARD L. BRADLEY, Social Security Administration KATHRYN LYNN CATES, M.D.U.S. Department of Veterans Affairs FRANCIS CHESLEY, Agency for Healthcare Research and Quality ROGER CORTESI, U.S. Environmental Protection Agency PATTY DECOT, U.S. Department of Defense SALLY FLANZER, Agency for Healthcare Research and Quality 2 DEBORAH HOLTZMAN, U.S. Department of Health and Human Services DAVID LePAY, M.D., Ph.D.Food and Drug Administration AMY PATTERSON, National Institutes of Health LAWRENCE UHTEGNIST ALSO PRESENT FROM OFFICE OF HUMAN RESEARCH PROTECTIONS KELLEY BOOHER KRISTINA BOOROR MICHAEL CAROME JULIA GOREY IVOR PRITCHARD KEVIN PROHASKA IRENE STITH-COLEMANO 3 A-G-E-N-D-A Opening Remarks . . . . . . . . . . . . . . . . . .3 Introduction of New Members . . . . . . . . . . . .3 Reports of Issues, Dr. Schwetz. . . . . . . . . . .6 Recognition of Departing Members. . . . . . . . . 11 Swearing in Ceremony. . . . . . . . . . . . . . . 17 Overview of Charges to Subcommittee . . . . . . . 19 Approval of Minutes . . . . . . . . . . . . . . . 20 Children's Subcommittee Report. . . . . . . . . . 22 Public Comment. . . . . . . . . . . . . . . . . .158 Cami Gearhart, Quorem OHRP's Guidance on Adverse Events and Unanticipated Problems. . . . . . . . . . . . . . . . . .164 Subpart A Subcommittee Report . . . . . . . . . .217 4 1 P-R-O-C-E-E-D-I-N-G-S 2 8:38 a.m. 3 CHAIRMAN PRENTICE: Okay. Good morning, 4 everybody. We're going to get started. 5 Welcome to the Third SACHRP meeting of 6 the year 2005. 7 So we're going to go through the normal 8 routine of going through the charter for anybody who 9 is not familiar with SACHRP. As you know, our charter 10 which was extended on September the 8th, 2004 requires 11 SACHRP to deliberate on various issues pertaining to 12 protection of human subjects and advise the Secretary 13 of HHS with particular emphasis on special 14 populations. And I'm sure you'll recognize the fact 15 that a great deal of our work has dealt with special 16 populations, in particular with children and 17 prisoners. 18 I'd like to now move into the introduction 19 of new members. These are the members of SACHRP, and 20 the two new members that we have are Dr. Neil Powe and 21 Dr. James Powell, who is here. Dr. Neil Powe is not 22 here. The rest of the SACHRP members, of course, are 5 1 familiar to you. 2 I'd like to once again recognize the 3 partnership between SACHRP and OHRP. And we really 4 appreciate the leadership and role and Dr. Bern 5 Schwetz, Director of OHRP. We could not be successful 6 without this partnership. As you very well know, OHRP 7 provides staff and expert advice for all of our 8 subcommittees, so we really appreciate that. 9 Also, Cathy Slatinchek, the Executive 10 Director of SACHRP took a brief absence and now is 11 back with us. She apparently saw the light of not 12 working for other areas of the Federal Government. 13 So, Cathy, we're delighted to have you back, 14 obviously. 15 Kelly, once again thanks very much for 16 everything that you do. You keep us time, you get us 17 here, you make all the arrangements. So we're very, 18 very appreciative. 19 I also want to recognize all of the ex- 20 officio members of SACHRP. That's also a partnership 21 and they meet regularly with OHRP staff on various 22 issues. As a matter of fact, tomorrow is going to be 6 1 largely devoted to priority discussions involving ex- 2 officio members and SACHRP. 3 Next, I would like to invite Bern Schwetz 4 to give us his report on the issues. Bern, I assume 5 you're going to deliver it from there? 6 DR. SCHWETZ: Thank you, Ernie. 7 And good morning to all of you. 8 As I put together a list of things that I 9 would comment on, it seemed that there has been a lot 10 that's happened in the last three months since August 11 1st. So I'll kind of quickly go through a list of 12 things here. 13 One of them is, as you heard in the news, 14 the FDA lost its Commissioner and now has an acting 15 Commissioner. I raised this not as any kind of a flag 16 or concern, but I raise it to assure you that we will 17 continue to work as closely as we can with the FDA 18 regardless of who is in the Commissioner's office to 19 have a partnership with our sister agency in this 20 regulatory arena. So as far as I'm concerned, the 21 change in the Commissioner's office hasn't changed our 22 working relationship has it relates to human subject 7 1 protection. And I don't anticipate or intend that it 2 would change. 3 Another thing is that OHRP announced in 4 this time that it is no longer in the activity of 5 crediting research protection programs. And I don't 6 think any of us knows for sure what the impact of that 7 is, but it again doesn't affect the OHRP opinion about 8 the support for accreditation as a process that in the 9 long run will be helpful to protecting human subjects. 10 So, again, this doesn't cause us to lose any 11 confidence in the accreditation as a process and there 12 are some people who think this makes it a little 13 simpler. But, nonetheless, our support of 14 accreditation as a process that will help protect 15 human subjects is as strong as ever. 16 OHRP suspended the assurance of a 17 university, Gothenberg University in Sweden. In it's 18 based on problems with IRB minutes, with continuing 19 review, with the availability of SOPs. And the impact 20 of this is the same as a suspension here in the U.S. 21 that no federally funded human research to which the 22 FDA applied can be continued. That had to be 8 1 suspended. So that happened about a month ago and 2 there has not been much attention to it in this month 3 or a suspension, which is interesting. 4 There have been a number of guidance 5 documents that have come out since August 1st, our 6 last meeting. One of them was our draft guidance on 7 adverse event reporting. It has been up on our website 8 since October 11th. And we're seeking input for this 9 90 day period after August 11th. And Dr. Carome will 10 be talking in more detail about this this afternoon. 11 So this was a biggie for us to get this document out, 12 to get it on our website for comment. 13 In addition, we have put up information in 14 the IRB review of clinical trial websites, which is a 15 question of increasing frequency. We continue to 16 believe that part of our education function can be 17 accomplished by sharing with you from our website the 18 questions that we get or that we think we should get 19 to help explain things and answering them on our 20 website. So the frequently asked questions and the 21 answers will continue to be a tool of education for 22 us, and most of what's gone up in the last couple of 9 1 months has to do with the questions that are asked 2 about research involving children. 3 We have also put up a document on OHRP's 4 compliance oversight procedures and updated that for 5 evaluating institutions as well as have updated the 6 common finding document on our website. So I 7 encourage you to look to those. 8 Switching from our guidance, EPA proposed 9 a rule in this last quarter, Protections for Subjects 10 in Human Research. So it was published in the Federal 11 Register on September 12th and they're receiving 12 comments until December 12th. This is a significant 13 step forward for EPA. And it's something that you 14 should be aware of, not just you but people broadly 15 should be aware of. And to the extent that it is 16 important that you submit information, answers, 17 comments that's why it has been published. 18 As I mentioned last time we have put up on 19 our website some information that hasn't been 20 available before on international regulations. That 21 has been expanded and updated and there's much more 22 information on the website now than the last time I 10 1 mentioned it. We are getting a lot of positive 2 feedback on that being a helpful set of information. 3 And I would just encourage you to remember to use it, 4 because that's why we have gone to the effort of 5 pulling this together and the intent to keep it up to 6 date. So check it out and use it to your benefit. 7 The last thing that I will mention is that 8 OHRP has evaluated a new element, a new approach 9 toward quality improvement, our quality improvement 10 activities. And it's to put on quality improvement 11 workshops. This is an original workshop for 12 institutions with HHS supported research. A small 13 workshop of no more than 50 people in attendance with 14 a similar number of institutions or one to two people 15 from an institution. So it's not 50 people from one 16 institution. 17 It's meant to be hands-on interactive 18 educational experience that will allow the 19 participants to improve their human subject protection 20 programs, their research protection programs in their 21 institutions by going through IRB activities, 22 firsthand experience, learning from other people, 11 1 learning from OHRP people who have learned from all of 2 you. 3 We have just had one of these in the 4 Baltimore area within the last few days, and the 5 participants said it was a valuable experience, and 6 given the opportunity they would attend another one. 7 So that's a good sign. And we intend to expand this. 8 So rather than do a quality improvement site visit at 9 your institution, this is meant to bring in several 10 dozen institution representative to hear about this in 11 one setting and go through it in a couple day meeting 12 with firsthand experience. 13 So with that list, Ernie, I'll turn it 14 back to you. 15 CHAIRMAN PRENTICE: Thank you, Bern. 16 The next part of our program is the 17 recognition of departing members and the swearing in 18 ceremony. 19 First let's go with the recognition of 20 departing members. As you know, a federal advisory 21 committee has rules that require term limits, and 22 unfortunately we have three people who have been very 12 1 active on SACHRP from the beginning whose term has 2 ended. And I would like to recognize those three 3 individuals, one of whom is here, the other two are 4 not here. But I will also say a few words about them. 5 And, Bern, would you come up here with me, 6 please. 7 First of all, I would like to recognize 8 Tom Adams. Tom, would you come up here, please? 9 Tom is the CEO of ACRP. I'm sure all of 10 you know that. ACRP is the world's largest 11 organization for clinical research professionals. And 12 Tom has been at the helm for quite some time and made 13 remarkable progress in developing and involving that 14 organization. 15 We're delighted that you have been a 16 member of SACHRP for as long as you have been. We 17 regret that you're leaving, but you know you're really 18 not leaving because you're just down the street. So we 19 plan on calling upon you. 20 Tom has been involved in a lot of our 21 activities here, but particularly on the HRPP 22 Accreditation Subcommittee and has brought to the 13 1 table a political astuteness that most of us do not 2 have. Perhaps you get that by living in Washington as 3 opposed to Nebraska. And organizational skills that 4 we really appreciate. 5 So, Tom, we're very grateful for 6 everything that you've done for us. 7 MR. ADAMS: Thank you. 8 CHAIRMAN PRENTICE: And we have a plaque 9 for you. 10 And I would like Bern to say a few words 11 before I hand you the plaque. 12 DR. SCHWETZ: The first few years of a 13 committee like this I think is different than any 14 other of the time of the committee, because it's a 15 fixed group and there is a camaraderie and a level of 16 support that's different then at any other time. And 17 we have certainly benefitted a lot, Tom, from the 18 relationship that you have created with us and with 19 the whole Committee. And I certainly would agree with 20 Ernie, you have a perspective that has always been 21 valuable to hear. And you helped push things at the 22 right time. In addition to help pushing things at 14 1 all, it's good to have people who have that sense of 2 what's important to move and what is less important. 3 And you seem to have a good sense of that. 4 And in addition, you and your organization 5 represent an element of this enterprise that is 6 extremely important to us, and it was very helpful to 7 have that perspective on the issues that we've been 8 looking. 9 So, thank you very much, Tom, for all the 10 help that you have been. 11 MR. ADAMS: Thank you, Bern. 12 CHAIRMAN PRENTICE: Tom, if I may, I'd 13 like to read the letter to you from Michael Leavitt, 14 Secretary of HHS. 15 "Dear, Mr. Adams: Your appointment as a 16 member of the Secretary's Advisory Committee on Human 17 Research Protection has ended. I would like to take 18 this opportunity to thank you for serving as a member 19 of this Committee. You have provided a valuable 20 service to the Department during your tenure as a 21 member of the Committee. 22 The advice and counsel you provided have 15 1 been a significant contribution to enhancing the focus 2 of the Department to better address the concerns and 3 issues impacting the protection of human subjects in 4 research. I truly appreciate the level of dedication 5 and loyalty you have demonstrated in assisting 6 departmental efforts to address the many matters that 7 impact this important area of public health and 8 science. 9 Although your appointment to the Committee 10 has ended, it is hoped that we may be able to call 11 upon you for further assistance and advice if the need 12 arises, and the need will arise." 13 Thank you. 14 MR. ADAMS: Thank you very much. 15 (Applause). 16 CHAIRMAN PRENTICE: All right. We have two 17 other departing members, Mark Barnes and Bob Hauser. 18 Mark Barnes, as you know, is an attorney 19 who specializes in health law, but more than that he 20 is an expert in the area of human research protection. 21 He has made many contributions to SACHRP, and indeed 22 to the entire IRB community. 16 1 During his tenure on SACHRP he was the co- 2 chair of our Subpart C Subcommittee which looked at 3 additional protections for prisoners who are research 4 subjects. 5 He was also our resident HIPAA expert. And 6 he was instrumental in drafting the recommendations on 7 HIPAA that were sent to the Secretary. 8 I think every federal advisory committee 9 should have a lawyer like Mark Barnes. He kept us on 10 our toes. He questioned. He'd never let Celia get away 11 with anything. And we're going to miss him. 12 So unfortunately, he had a crises in his 13 law firm in New York and he could not be here. So I 14 would like to publicly recognize his contributions and 15 our gratitude to him. So let's just give him all a 16 hand in absentia. 17 (Applause). 18 CHAIRMAN PRENTICE: And we will be sending 19 him a plaque and a letter from the Secretary. 20 The third member who has departed is Bob 21 Hauser. As you know, Bob Hauser was a cardiologist 22 from Minnesota. He provided SACHRP with very much 17 1 appreciated expert medical advice. Certainly the 2 issues that we deal with interface between science, 3 medicine and protection of human subjects and we do 4 need that sort of expertise. So we're very, very 5 grateful for the time that he spent with us. And 6 we're going to miss him. 7 So let's give Bob a hand. 8 (Applause). 9 Next, it's my pleasure to have a swearing 10 in ceremony. And there are actually two individuals 11 who are going to be sworn in. One is our newest member 12 of SACHRP, which I'm going to tell you a little bit 13 about him, and another member who did not get sworn in 14 earlier is an old member of SACHRP that fulfilled a 15 departing member's term and Ada Sue, unfortunately, is 16 going to get sworn in because she's going to be sworn 17 out because her term ends in end of December. 18 But first let me tell you a little bit 19 about Dr. James Powell. Dr. James Powell is a native 20 of Birmingham, Alabama. He attended Cornell 21 University Medical College in New York City where he 22 received his doctorate of medicine degree. 18 1 In 1982 you joined the pharmaceutical 2 industry at what is now Procter & Gamble 3 Pharmaceuticals, and he's held multiple positions over 4 the years, most recently as Senior Medical Director 5 and head of the Clinical Pharmacology and 6 Pharmacokinetics Department. And what he does in this 7 particular capacity includes managing the company's 8 global clinical pharmacokinetics programs and early 9 human testing of new prescription pharmaceutical 10 products. 11 I won't go into all of his bio, except to 12 sort of end my comments by telling you that in August 13 2002 the National Medical Association awarded Dr. 14 Powell with the first James H. Powell Clinical 15 Research Leadership Award for his efforts leading to 16 improved involvement of African American in biomedical 17 and clinical research. And then in November of 2003 18 Dr. Powell was awarded the designation of certified 19 physician investigator by the American Academy of 20 Pharmaceutical Physicians. 21 And, Dr. Powell, you're very much welcome 22 here at SACHRP. I'm really looking forward to 19 1 interacting with you over the next ten years or so. 2 So Dr. Powell, would you please come up 3 here. 4 And Ada Sue, who needs no introduction, 5 would you please come up here as well. 6 And, Anita, we're going to let you take 7 over. 8 (Whereupon, Dr. James Powell and Ada Sue 9 Selwitz sworn in.) 10 (Applause). 11 CHAIRMAN PRENTICE: Next I'm going to go 12 through the overview of the charges to SACHRP 13 subcommittees. As you know, we have two subcommittees 14 who are in place. There is the SRIC, a subcommittee of 15 research involving children and they're looking at all 16 aspects of Subpart D in order to ensure that children 17 who participate in research are neither under 18 protected nor over protected. And the co-chairs are 19 Celia Fisher and Susan Kornetsky. 20 And I have to tell you that I'm so 21 impressed with all of the work that you and your 22 Subcommittee have done. It's been a laborious process. 20 1 You spend many, many hours in Subcommittee meetings 2 and preparing reports. And I really think that you've 3 done fantastic work, and the product you're producing 4 is going to be extremely valuable to the research 5 community. So thanks for your efforts, Celia and 6 Susan. 7 We have the newest Subcommittee, Subpart 8 A. It's under the co-chairmanship of Felix Gyi and Dan 9 Nelson. And their charged with reviewing all 10 provisions of the basic protections of human subjects, 11 Subpart A of 45 CFR 46. They're also asked to look at 12 OHRP guidance documents and provide recommendations 13 for consideration by SACHRP with a goal of enhancing 14 protection of human subjects while reducing 15 unnecessary regulatory burdens that don't really 16 contribute to protection of human subjects. 17 They've spent an awful lot of time working 18 very hard since their initial meetings. And we're 19 looking forward to their reports at this meeting and 20 subsequent meetings. 21 Next, I would entertain a motion of 22 approval of the minutes from the August 1st and 2nd 21 1 2005 meeting. 2 MR. ADAMS: So moved. 3 CHAIRMAN PRENTICE: Any further 4 discussion? 5 Those in favor? Any opposed? Any 6 abstentions? 7 The minutes are approved. 8 Now, you all did read them, did you not? 9 And memorized them? Good. That's what I like to 10 hear. 11 Let's go through what we're going to do 12 today. We've already done some of it. 13 At 9:05, five minutes from now, Celia, 14 we're going to have our report on the Subcommittee on 15 research involving children. And we will go from 9:05 16 to 10:35. 17 We'll take a break. And then we'll 18 continue until 12:00 as necessary. Have lunch. 19 And then have a public comment period 20 between 1:00 and 1:30. If anybody in the audience 21 wishes to address SACHRP, you can certainly sign up on 22 a list. We're filling that. You have an opportunity 22 1 to decide at 1:00. 2 At 1:30 we're going to have Dr. Michael 3 Carome, from OHRP addressing us on what Bern mentioned 4 earlier, the draft guidance on adverse events and 5 unanticipated problems. This is a culmination of the 6 initial panels that we had at the very beginning of 7 SACHRP on the adverse event problem. So this has been 8 OHRP's response to those early discussions by SACHRP. 9 So we're looking forward to that report. 10 Then at 2:15 we're going to have the 11 Subpart A Subcommittee report delivered by Felix Gyi 12 and Dan Nelson. We'll take a break between 3:00 and 13 3:15, and then they will continue their report with a 14 wrap up at 4:30 to 5:00. 15 So, we're actually three minutes early, 16 Celia. So why don't we get started. 17 DR. FISHER: Okay. So we're back again in 18 our discussions with the Children's Subcommittee. We 19 paid careful attention to the feedback from SACHRP 20 last time, and I think we've come up with some very 21 practical and pertinent recommendations. 22 These are the individuals on our 23 1 Committee, who are absolutely excellent. And nothing 2 we do could possibly even be envisioned without their 3 input. And we also had wonderful ex-officio members 4 who really helped us this time, especially with 5 respect to the FDA harmonization question. 6 So our meeting goals for this particular 7 meeting was to identify terminology and procedures in 8 Subparts A and D that might require clarification or 9 consensus concerning parental permission and child 10 assent. So here's just a brief overview of how this 11 talk and our recommendations are organized. 12 We're going to start with waiver of parent 13 permission and look at that both with respect to the 14 116 regulations as well as the 408(c). Then we'll 15 move on to the nature of child assent, once again 16 looking at both Subpart A and Subpart D regulations. 17 And then we're going to move on to OHRP FDA 18 harmonization issues. 19 So, at the general overview, one of the 20 things that we were thinking about is the federal 21 regulations recognized increased vulnerability of 22 minors to research with and to participation autonomy. 24 1 And that the protection of minors is addressed in both 2 Subpart A and Subpart D, even though it's explicit in 3 Subpart D. 4 The risk protections are something that we 5 have been looking at in our last wave of 6 recommendations regarding definitions of risk. And so 7 we have looked at that under Subpart D. Subpart A 8 requires minimization of risks and maximization of 9 benefits for all research participants. And then, as 10 you know, Subpart D then offers special protection by 11 having special procedures for different levels of 12 risk. 13 So what we began to realize, because 14 sometimes parental permission and child assent can be 15 confounded by discussions about risk. And so we wanted 16 to really make a distinction between the protection 17 against risk and the preservation of autonomy and self 18 governance. And so that's why we've made this 19 distinction here because what we're looking at now are 20 issues related to autonomy and lack of thereof 21 sometimes when you're talking about children. 22 So with respect to autonomy protection 25 1 Subpart A regulations require the informed consent of 2 all subjects with some exceptions for research 3 involving no more than minimal risk. Whereas, Subpart 4 D provides additional protections for children by 5 requiring parent/guardian permission and participation 6 asset with some exceptions for research involving all 7 levels of risk, not just minimal risk. 8 Okay. So with that as a background, we 9 want to go to waiver of parental permission. The 10 first thing we looked at was 116(d) under Subpart A. 11 I think the issues here with respect to informed 12 consent has to do when the IRB can approve a consent 13 procedure which does not include or can actually waive 14 some of the requirements. And the important point for 15 us to consider here is that it's always minimal risk. 16 We thought that was pretty clear. But the two phrases 17 that sometimes seem to confuse IRBs and investigators 18 is what does "will not adversely effect the rights and 19 welfare of the subjects" mean and what does "could not 20 practicably be carried out without a waiver" mean. 21 So we attempted to address this issue only 22 with respect to parental permission and child assent. 26 1 Okay. So the first thing we're going to 2 be looking at is what does "will not adversely effect 3 the rights and welfare of the subjects" mean and what 4 kind of criteria can IRBs use in some kind of 5 consistent fashion that would help to identify when a 6 waiver was or was not appropriate of parental 7 permission. 8 So these were our recommendations. 9 Recommendation one has to do criteria for determining 10 "adversely effect the rights and welfare of the 11 subjects," and there are three criteria. 12 The first is that the IRB needs to 13 consider whether or not a waiver would be inconsistent 14 with federal, state or local laws pertaining to 15 parent/guardian permission. 16 Second, they should look at local norms 17 with respect to the role of parents vis-…-vis their 18 children. 19 And finally, seeing whether ensuring there 20 are appropriate mechanisms to protect the rights and 21 welfare of child participants. And we just want to 22 keep reminding you that when we're talking about 27 1 116(d) we are only talking about minimal risk 2 research. Okay. 3 So we wanted to give examples. So what do 4 we mean by relevant laws? Well, for children there's 5 the HIPAA Act, which is relevant to everybody but 6 there are special guidelines for those who do not have 7 legal authority to give consent. There's PPRA, which 8 is the Protection of People's Right Amendment that 9 pertains directly to the types of research in which 10 parents must have information about. And there is 11 FERPA, which has been around for a much longer time 12 that is relevant to child records. And I'm sure there 13 are many more, but these are the ones that we 14 identified. So that's an example of the type of laws 15 that an IRB needs to consider. 16 Second, what do we mean by local norms? 17 Well, has the investigator provided a reasonable 18 argument that the waiver does not violate the norms of 19 the community from which the child will be recruited 20 and how could they demonstrate that? What's 21 reasonable? Well, they may present that they have a 22 community advisory board whose advice was sought. It 28 1 might be that there's an unaffiliated nonscientific 2 IRB members who isn't present to represent the 3 participant population. And there may be many other 4 ways to ensure that the norms of the community have 5 been considered. 6 What do you mean by alternative 7 mechanisms? Is the child old enough to give informed 8 and voluntarily asset? That could be one alternative 9 mechanism. 10 Another is whether or not there's an in 11 dependent participant advocate who is available. 12 So here is an example of how this criteria 13 might be used. The example is research to determine 14 whether food intake patterns match Census track 15 patterns of obesity. PI requests a parent/guardian 16 permission waiver to administer a survey on soft drink 17 and fast food intake to 2,000 middle school students 18 in different socioeconomic communities. So remember, 19 this is minimal risk research. 20 So looking at the criteria the first one 21 is laws. There is no laws in this district or state 22 that require parental permission for questions about 29 1 nutrition. 2 With respect to local norms, the 3 investigators have provided evidence that they worked 4 with local PTA in developing the procedures. 5 And with respect to alternatives, the 6 middle school children are old enough to understand 7 the assent information, and the investigators 8 demonstrated that adequate steps are going to be taken 9 to ensure that the children will not feel coerced into 10 participating. 11 Here's an example of when it would not be 12 waived based upon our three criteria. Laws. For the 13 same fast food study the investigator also proposes to 14 correlate eating patterns with middle school student 15 grade point averages. In that regard FERPA does not 16 permit school records to be provided without written 17 permission for parents. So under 116(d) this would 18 not be waived. 19 Community norms. An example, fast food 20 questionnaire will contain questions about food, e.g. 21 pork that are prohibited in the orthodox religious 22 community in which the study will be conducted. 30 1 Parents in the community are concerned that such 2 questions will send a message to their children that 3 their religious views should not be respected or that 4 the children will think that their religious faith is 5 secretly being tested. 6 And an appropriate mechanism would be that 7 investigators wished to conduct a fast food study with 8 preschoolers in which there is little evidence that 9 the preschoolers would voluntarily not only not 10 understand the assent information, but not think that 11 they had to participate. 12 Okay. So that was under 116(d) waiver of 13 parental permission. 14 First the event. That's right. Because 15 reasonable is (d). Okay. 16 So now we're going to look at under 116(d) 17 could not practicably be carried out without the 18 waiver. What does practicably mean, and why it was 19 such a hard word to pronounce put into the regulation? 20 So here's our recommendation. To determine 21 whether parental permission can be waiver under 116(d) 22 because the research cannot be practicably carried 31 1 out, the IRB should require investigators to provide, 2 and here are three criteria. 3 A reasonable argument that scientific 4 validity would be compromised if parental permission 5 was required. Once again remember this is only for 6 minimal risk research. 7 Second, a reasonable argument that 8 alternative methods to obtain parent/guardian 9 permission are not feasible. 10 And third, a rationale for why the 11 research could not be conducted with a population for 12 whom parent/guardian permission could be practicably 13 carried out. 14 So what's an example utilizing our 15 criteria of the parent permission waiver that's 16 appropriate under practicably? The PI proposed to 17 waive parental permission for national study of diet 18 and after school activities to predict Census track 19 concentrations of middle school children's respiratory 20 disease. 21 The first criteria is whether or not it's 22 necessary for scientific validity. A large random 32 1 sample of children is necessary for statistical power. 2 3 Are there alternative methods? Census 4 track neighborhoods vary with respect to the ability 5 to contact parents through telephone directory or 6 other measures. So there are not alternative measures 7 to obtain parental permission in a way that would not 8 sacrifice scientific validity. In alternative 9 populations there are none. All Census tracks must be 10 included for the data to be meaningful. 11 So that would be how the criteria would be 12 used to approve this kind of minimal risk research. 13 But we wanted to make sure that there were 14 understood limitations on practicably. So our third 15 recommendation is guardian permission should never be 16 waived under 116(d) for convenience nor waived solely 17 for reasons of cost or speed if so doing so dilutes 18 protections of subject's rights and welfare. 19 For example, IRBs may not waive 20 parent/guardian permission because of funding 21 limitations if those limitations result in procedures 22 that do not provide the same degree of subject 33 1 protections that better funded research would provide. 2 Okay. Now we also thought that in 3 discussing the waiver of parental permission for 4 minimal risk research it was very important to 5 readdress the passive consent issue because so many 6 investigators do not seem to understand that there is 7 no such thing as passive consent. And sometimes, I 8 guess, IRBs approve it because I still see it written 9 up in the literature that we obtain passive consent. 10 So what is passive consent? That's when 11 parent/guardians are sent forms describing the 12 research and asked to respond only if they do not want 13 their child to participate. 14 The passive consent fallacy. The fallacy 15 is that failure to respond in the negative indicates 16 that parental consent has been obtained. And, 17 unfortunately, you see in articles that 90 percent of 18 parents agreed: Based upon a passive consent 19 procedure in which they obviously got that, 10 percent 20 who said no. 21 So our recommendation is that SACHRP 22 reaffirm, because this is already in regulation, but 34 1 SACHRP reaffirms that passive consent given the 2 definition is not an approvable mechanism for 3 satisfying the parent/guardian permission requirement 4 under 116(d) or 408. When parent/guardian permission 5 meets the requirement for waiver under either of these 6 regulations, and IRB should consider whether parental 7 notification and right of refusal is appropriate. So 8 the distinction here is not with the methodology of 9 sending home forms that might say, you know, you have 10 the right to refuse and this is what we're doing. The 11 motivation for this recommendation is to underscore 12 the importance of the IRB's decision that they are 13 waiving parental permission in doing this and that the 14 investigator has to make the case for the waiver. 15 So an example of how the criteria would be 16 used for recommendation four would be PI proposes 17 administer dietary and after school activity 18 questionnaire to middle schoolers during health class. 19 Participation is voluntary. Adequate student assent 20 will be obtained. Research is minimal risk and cannot 21 be practicably carried out if parental permission is 22 required. The IRB waives the requirement for parental 35 1 permission under 116(d) but also recommends a letter 2 is sent home to the parents informing them about the 3 research and providing a contact number if they had 4 questions or did not want their child to participate. 5 Okay. So now we're going to turn to 6 waiving guardian permission under 408(c). What is 7 408(c)? In addition to the provisions for waiver 8 contained in 116, which is what we've just spoken 9 about, the IRB can decide to waive aspects of parental 10 permission if it is not a reasonable requirement. And 11 the only example given is for neglected or abused 12 children. So there are two issues there. One is what 13 is reasonable. And number two is that IRBs and 14 investigators have felt constrained because there is 15 an example in the regs. And so it seems that their 16 people restrict what they're waiving for, only to this 17 very specific neglected or abused children. And we 18 wanted to flush out how the regulations could be 19 interpreted without simply confining one's self to an 20 example. 21 So we thought it was important at this 22 point to once again raise the distinctions between 36 1 116(d) minimal risk research and 408(c). So while 2 116(d) is limited to minimal risk, 408(c) criteria 3 applies to minimal as well as greater than minimal 4 risk research. 5 For minimal risk research the IRB approval 6 of waiver under 116(d) is sufficient. And we thought 7 that was very interesting because a lot of times IRBs 8 and investigators don't realize that; that they can 9 waive parental permission under 116(d). And also 10 alluding to 408(c) they can use the criteria in 116(d) 11 because it's minimal risk. However, minimal risk 12 research that does not meet parent/guardian permission 13 waiver under 116(d) may meet waiver requirements under 14 408(c) because 408(c) addresses harm posed by 15 parent/guardian permission itself. 16 So, our first question was outside of 17 neglect or abuse when can parental permission be 18 waived under the term reasonable requirement to 19 protect the subject. This is our fifth recommendation 20 for helping to define that. 21 In considering parent/guardian waiver 22 under 408(c) IRB should consider justifications for 37 1 not a reasonable requirement beyond the example of 2 neglected or abused children given within the 3 regulation and include instances in which 4 parent/guardian permission would jeopardize subject 5 welfare or fail to provide additional subject 6 protection. 7 Recommendation six. This is our criteria 8 for reasonable requirement to protect the subjects. 9 Assuming that an appropriate mechanism for protecting 10 the children is provided, because that's the other 11 part of 408(c), the IRB may waive parent/guardian 12 permission under 408(c) applying the following three 13 criteria. Informing parents will harm the child or 14 parent permission may not be in the child's 15 permission, or research involves in adolescents and is 16 important to the population health, subjects have 17 consent capacity, there is voluntary participation and 18 the procedures are commiserate with state law. Now 19 we're going to take you through by each of those 20 criteria. 21 Not a reasonable requirement applying 22 criteria one. The investigator has offered a credible 38 1 argument that serious physical social or psychological 2 harm may come to child subjects if parent/guardian 3 permission are informed about the reason for the 4 study. An example we would give is PI seeks to 5 identify patterns of psychological risk and resilience 6 in high school students who identify themselves as gay 7 or lesbian. That's put in here, and Susan had in 8 there. And they have not revealed their sexual 9 identity to their parents. 10 The second criteria for not a reasonable 11 requirement. The investigator has offered a credible 12 argument that parent/guardians may not make permission 13 decisions that are in the best interest of the child. 14 An example might be the PI seeks to study coping 15 behaviors of adolescents who have joined an Al-Anon 16 group because of alcoholic parent, and that parent 17 consent or permission might not be in the child's best 18 interest. 19 Now, not a reasonable requirement 20 requiring adolescents. Here we tried to address an 21 issue that's been harping investigators and IRBs for 22 a long time with respect to the Mature Minor statute 39 1 in the states and how that does or does not relate to 2 the waiver of parental permission for some types of 3 research. 4 So first under this the participants must 5 be adolescents. And then are the four criteria: 6 The research is important to the health 7 and well being of the subject population; 8 The PI has made a reasonable argument that 9 the subject population is capable of understanding the 10 research and their research right; 11 Adequate protections are in place to 12 assure the voluntary nature of participation, which of 13 course is in the regulation itself, and involves 14 experiences or procedures that are reasonably 15 commiserate with those inherent in treatment that 16 state laws permit adolescents to receive without 17 parent/guardian permission. 18 Now, I want to review why we're using that 19 language and what the issue, the difficult issue is 20 here. 21 A mature minor is someone who has not 22 reached adulthood as defined by state law, but who 40 1 according to state law may be treated as an adult for 2 certain purposes. For example, depending on the age, 3 consenting to treatment for venereal disease, drug 4 abuse or emotional disorders. According to 46 402 5 mature minors may not be considered children under 6 Subpart D if applicable laws of the jurisdiction 7 permits them to provide independent consent to the 8 procedure for which the research is evaluating. 9 However, few states specifically address the 10 participation of minors who are adolescents in 11 research. So a lot of times the state mature minor 12 rule is silent with respect to research. So there's a 13 quandary here in terms of whether or not, how it 14 relates to an IRB approval of parental waiver. 15 So here's an example. Parent permission 16 not a reasonable requirement. Here's the study. A PI 17 applies for parental waiver to study adolescent girls' 18 attitudes toward and use of different forms of birth 19 control. Participants will be recruited from -- now 20 the important point here is that this is not a medical 21 study which is using birth control devices which might 22 come under the mature minor rule in the particular 41 1 state if it said that these minors could receive this 2 without parental permission. So this is related to 3 that procedure, but let's say in this particular state 4 is silent on research involving these types of 5 procedures. 6 So participants will be recruited from a 7 clinic serving teenage girls 14 years and older who 8 are permitted by state law to receive gynecological 9 services and birth control. 10 How do we apply the criteria to this 11 study? First, the research is important to the health 12 and well being of adolescent females who are sexually 13 active. 14 Second, there is empirical evidence 15 demonstrating that by age 14 adolescents are capable 16 of understanding informed consent at adult levels. 17 Third, the PI has assured that during 18 recruitment it is clear to the teenagers that the 19 participation in the study is not related to their 20 treatment and a decision not to participate will not 21 jeopardize their ability to get services. 22 And finally, asking subjects about their 42 1 sexual practices and use of birth control is 2 reasonably commiserate with questions asked during 3 gynecological services that are permitted by law that 4 the 14 year old can receive without parental 5 permission. 6 And just to back track for a moment, the 7 age 14 is something that we've selected based upon, 8 for example, the Institute of Medicine's excellent 9 summary of all the literature out there on 10 adolescents' ability to provide assent and consent. 11 Okay. So, now we go to the applicability 12 of the emergency waiver to the waiver of 13 parent/guardian permission. You'll remember we talked 14 about this specifically last time. We did eliminate 15 the second part, which rightly so didn't seem to make 16 any sense. But this is the first part of the 17 recommendation that I think actually there was SACHRP 18 agreement about. 19 So the emergency research waiver, as you 20 all know, does permit waiver of parent/guardian 21 permission and child assent as long it meets all these 22 very specific and stringent criteria. 43 1 The issue that the SRIC wanted to raise, 2 and for SACHRP to make a recommendation for, is that 3 the emergency guidelines should also be applied to be 4 parental permission waiver when parent/guardians are 5 present under special circumstances. The rationale is 6 based upon the fact that based on what is in the 7 emergency regulations that if you look at (2)(ii) the 8 intervention involved in the research must be 9 administered before consent from the subject's legally 10 authorized representative is feasible, and, there is 11 no reasonable way to identify perspectively the 12 individuals likely to become eligible for 13 participation in the research. 14 So drawing upon those parts of the 15 emergency regulation we felt it appropriate under some 16 circumstances and very critical to be able to waive 17 parental permission. 18 Here's the hypothetical example. Clinical 19 equipoise exists between two emergency treatments 20 administered at the time of hospital admission for 21 life threatening pediatric seizure disorder. A 22 randomized clinical trial will compare the efficacy of 44 1 the two treatments. There is no way to identify 2 prospectively children likely to become eligible for 3 the research and the time necessary to obtain 4 parent/guardian permission is not feasible because it 5 would create a treatment delay that could compromise 6 the child's health. So even though the parent is with 7 the child, if the physicians do not act immediately 8 the child's health would be jeopardized. 9 Okay. So now we move into child assent. 10 You want us to continue? 11 CHAIRMAN PRENTICE: Celia, I think it 12 might be appropriate to kind of split up your 13 presentation and respond to questions at this 14 particular point. 15 DR. FISHER: Absolutely. 16 CHAIRMAN PRENTICE: And, again, everybody 17 knows that I observe the prerogative of the Chair to 18 ask the first series of questions, if you don't mind. 19 In looking at waiver of parent/guardian 20 permission under 116(d) I've got a couple of 21 questions. One is the IRB must find and document 22 compliance with the requirements of 116(d). What 45 1 constitutes appropriate documentation? Is it 2 sufficient for an IRB to simply say well it meets 3 conditions one through four or do you have to actually 4 provide detail in the written record as to how the 5 waiver was justified? 6 DR. FISHER: Which one? 7 CHAIRMAN PRENTICE: I'm on slide 9. 8 DR. FISHER: Okay. 9 MS. KORNETSKY: I mean, Ernie, I think 10 it's like many other things. That there needs to be 11 some meaningful reflection somewhere that those things 12 were taken into consideration. Perhaps the ways 13 protocols are written that investigators can justify 14 how these things are met so that it's within the body 15 of the protocol, perhaps within the minutes. 16 CHAIRMAN PRENTICE: Okay. 17 MS. KORNETSKY: That would be my own 18 sense. 19 CHAIRMAN PRENTICE: Okay. Would you 20 consider adding that to your recommendations that 21 there should be a mechanism of documentation. You 22 don't have to prescribe what it is. 46 1 MS. KORNETSKY: Right. 2 CHAIRMAN PRENTICE: But it's simply not 3 sufficient to have a checklist that says well that 4 it's no more than minimal risk, the waiver will not 5 adversely affect the rights and welfare, etcetera? Do 6 you see where I'm going on that? 7 MS. KORNETSKY: Yes. No, I think 's 8 important. 9 DR. FISHER: And one of the things we 10 discussed at the meeting with respect to the type of 11 evidence is that for some situations there's not 12 empirical evidence. You may have not an empirical 13 evidence about norms. You may not have empirical 14 evidence about certain things. But that it's the 15 investigator's responsibility to provide a reasonable 16 argument with respect to how the research does address 17 any of the criteria. So I think documentation is very 18 important. 19 CHAIRMAN PRENTICE: Okay. 20 DR. FISHER: And it shouldn't be that the 21 IRB has to go and research all this themselves. I 22 think the Committee felt that very strongly. 47 1 CHAIRMAN PRENTICE: Okay. My second 2 question is when you have a waiver of parental 3 permission and a waiver of child assent, okay, and I'm 4 not talking about emergency circumstances. I'm talking 5 about a study that there's a request for both. Have 6 you considered that? 7 DR. FISHER: Yes. And that will come up 8 in the child assent. 9 CHAIRMAN PRENTICE: Okay. Then I would 10 also at some point like to talk about whenever 11 appropriate subjects would be provided with additional 12 pertinent information after participation. I don't 13 know if you get into that later on or not. 14 DR. FISHER: We do not because we felt 15 that was clear. We didn't feel we were going to be 16 addressing -- we didn't disagree with that. We just 17 did not -- 18 MS. KORNETSKY: That's one of the things 19 I think we didn't get into, and we can go back and 20 challenge the group whether that's really that 21 different for adults than children. But if there are 22 specific things that you have in mind, please bring 48 1 them up when we get to that discussion. 2 CHAIRMAN PRENTICE: Okay. When you talk 3 about not adversely affected and rights and welfare of 4 the subjects and then you provide some criteria and 5 it's to be the relevant laws. And there's some of 6 those that actually specify rights like, for example, 7 FERPA, right? Are there other specifications of 8 rights? Because in 46 CFR 46 there's actually really 9 no mention of what the rights of research subjects 10 are. It's implied by whether you get informed consent, 11 you know you minimize risk, etcetera. And then you 12 have to in the informed consent process you've got to 13 inform subjects that if they have any questions about 14 their rights as a research subject, they need to ask. 15 Okay. 16 Did your Subcommittee discuss what all of 17 those rights might be for a minor who participants in 18 research" 19 DR. FISHER: You know, this is something 20 actually over the years, and I think even when we were 21 in the IOM, we -- I know that in some of my research 22 I've tried to get information about is there a 49 1 national parent right. There isn't other than some of 2 these. And so we did not want to define parent rights 3 or rights of children outside of what might be 4 federal, state or local laws. And we didn't want to 5 be too explicit because we don't want to be limiting 6 to states or localities that have different types of 7 laws. But I think it's our impression that there's not 8 some kind of universal legalistic way of defining what 9 that is. 10 It was my understanding, and maybe I'm 11 wrong, but my understanding is is that when we tell 12 prospective participants that they call the IRB to 13 understand their rights, I've always interpreted that 14 as their rights within federal regulations. 15 CHAIRMAN PRENTICE: Okay. All right. I 16 have two more questions. On the slide pertaining to 17 local norms. The community perspective have been 18 sought, unaffiliated nonscientific IRB member is 19 present to represent the participant population. You 20 know, most IRBs have one to perhaps three community 21 representatives. And they don't necessarily 22 represent, obviously, all populations. Did your 50 1 Subcommittee consider utilizing a consultant as 2 opposed to a voting IRB member? 3 MS. KORNETSKY: I think this was really 4 just an example. I think that, yes. And if you think 5 that this will be interpreted the wrong way, we could 6 give other examples such as the community participant 7 asking for outside consultation. I mean, I don't 8 think that that will hurt. 9 CHAIRMAN PRENTICE: All right. I think 10 that would provide more flexibility for IRBs if you 11 did that. 12 DR. FISHER: Absolutely. Right. 13 CHAIRMAN PRENTICE: One the slide that is 14 recommendation three limitations on practicability. 15 I was struck by your clarifier at the end of the first 16 paragraph. We should not waive guardian permission 17 for the sake of convenience or reasons of cost or 18 speed. But then the caveat is if doing so dilutes 19 protection of subject's rights and welfare. What 20 happens if it doesn't dilute protection and the 21 investigator simply, you know for convenience or cost 22 sake, wants to request a waiver, which they often do? 51 1 What was the rationale for adding that qualifier? 2 DR. FISHER: The discussion, it was very 3 interesting. The discussion was that if we ruled out 4 cost or speed completely, there might be research that 5 was ethical that fully protected children, that could 6 be done in a way that was more efficient. And if we 7 did not include that, that kind of research would be 8 totally ruled out. 9 What we wanted to do was have RIBs be able 10 to with support from OHPR guidance say just because 11 you don't have a lot of money, we don't think these 12 protections are sufficient and we're not going to 13 approve them just because you say you don't have 14 enough money, or we want to get this done right away 15 because our grant's going to be over or something to 16 that effect. However, if it's more efficient to do 17 something, that doesn't mean it's unethical if in fact 18 all the protections are met. 19 CHAIRMAN PRENTICE: Okay. All right. The 20 floor is open and we'll follow the normal routine. 21 Raise your hand so that I can recognize you and we'll 22 try to do this in an orderly way. 52 1 Felix? 2 DR. GYI: I had some similar questions as 3 well, so forgive me for asking questions that are 4 redundant as to what Dr. Prentice has asked. 5 Let me go back to the local norms for a 6 moment, because there are a number of slides that the 7 recommendations addressed the issues of state and 8 local regulations. And from a central IRB 9 perspective, you know I wish that there were a set of 10 regulations that states would at least consistently 11 follow. I mean, there isn't a set of regulations that 12 we can point to on a regular and consistent basis, 13 especially with children. And so I wondered what the 14 Committee had thought about with respect to those 15 instances when the state regulations were silent? 16 Could you just address that first? 17 MS. KORNETSKY: Sure. This is an 18 interesting issue. And I have had opportunity to go 19 to different parts of the country and talk about 20 waivers of parental permission and have been very much 21 struck how in certain parts of country, and I think 22 this would be expected, that people feel more 53 1 comfortable and in other situations they would not 2 even be considered, even for some of this minimal 3 risk. And for a while as a proponent of this, you 4 know of allowing it, that bothered me. But when I 5 really thought about it afterwards, and it took me a 6 while, and I said you know that's the purpose of 7 having a local and cultural review. And I understand 8 how certainly from a central IRB it's a real problem. 9 But in the end I don't think there's something wrong 10 with that. 11 If there locally there is a group of 12 people for cultural or religious reasons that feel 13 that they don't want their kids doing anything without 14 their permission, then I would have a hard time 15 permitting a waiver within that area. 16 I mean, although I think we would desire 17 something to be applied, I'm not sure ethically how 18 that's practicable. 19 DR. GYI: I'm struck by this particular 20 topic, especially with regard to the Kennedy-Grieger 21 experience in the lead abatement study. And, you 22 know, even in that setting there was research that was 54 1 done that was reviewed by a local IRB. And the 2 decisions to move forward were retrospectively 3 criticized in a way that would, I think, raise that 4 question again of who decides. 5 DR. FISHER: Yes. As Susan just said, the 6 Kennedy-Grieger -- I don't want to rehash it and 7 probably don't even know it -- but part of that had to 8 do with the parents' understanding of what the study 9 was about, at least in the cases that were brought 10 forth. And part of our requirements actually can be 11 helpful with that because, you know, demonstrating 12 that there was a parent representative, either as a 13 consultant on the IRB or advisory group met together 14 to say this is what we're doing, do you think others 15 like you would understand this consent information 16 that that's what we're doing. 17 So we feel that that in fact would help 18 hedge against the perhaps lack of understanding that 19 might go on when permission was waived. 20 And getting back to Susan's point, we were 21 not going to turn around federal regulations that 22 respect the decisions of local IRBs and place them 55 1 locally. That doesn't mean that a centralized IRB 2 could not work. What it means is the centralized IRB 3 would need to be competent to be able to take into 4 account the local norms. 5 In addition, I don't think we'd want to 6 tell -- the states are so varied with respect to 7 mature minor rules that while centralized IRB are very 8 optimal for some instances, they would still have to 9 take into account how the research is going to be 10 performed across states. So I don't think that this in 11 any way takes away from the notion of having a 12 centralized IRB. But it points to criteria that that 13 central IRB would have to use. 14 DR. GYI: I still have a concern about 15 that. 16 DR. FISHER: Yes. 17 DR. GYI: Because I think it becomes 18 prohibitive for that oversight in a setting, and again 19 appreciating that this is the minimal risk category. 20 I think that it could become prohibitive in a way that 21 we don't mean for it to be in order to try to get that 22 local flavor, if you will. Especially in the absence 56 1 of state and local laws. 2 And I'll stop with that because I have 3 some other questions. 4 DR. FISHER: Sure. 5 DR. GYI: One other question of relevance 6 here. I'd like to just point out Dr. Prentice said 7 the recommendation was to not have the IRBs serve as 8 a verifier of certain information. I think that 9 that's what we talked about when we talked about 10 recommendation of the three; that somebody else be 11 held, the investigator be held accountable for that 12 verification. 13 DR. FISHER: Can I just say something. I 14 think there's a difference between verification and 15 documentation. I thought that Dr. Prentice was talking 16 about documentation and that the responsibility is on 17 the investigator to present his or her best case with 18 respect to these waiver criteria. It doesn't take 19 away whatever responsibility or initiative the IRB 20 wants to take with respect to verifying this 21 information. 22 DR. GYI: Good point. 57 1 CHAIRMAN PRENTICE: Yes. Felix, that's an 2 important clarifier. I really believe that 3 investigators ought to be accountable for justifying 4 a request for waiver. And given the IRB's sufficient 5 information where they can make a reasoned judgment. 6 What I have seen too often in the past is that the 7 investigator requests a waiver, there's absolutely no 8 justification whatsoever and the IRB has a checklist. 9 So if you look at the documentation, you don't know 10 either the investigator arrived at their decision or 11 how the IRB justified the waiver. 12 So, again, I believe the investigator 13 should be responsible for providing sufficient 14 rationale and justification. 15 But I do have one question for you, Felix. 16 And I don't know how often independent IRBs get 17 requests for waiver. Could you enlighten? I mean, I 18 know what happens at a local level, but do you get 19 such requests at Chesapeake or other independent IRBs 20 in which you're familiar with? 21 DR. GYI: I am not. And I think that 22 we're always going with that particular line of 58 1 thinking was that, you know, once we adopt 45 CFR 46 2 there is a potential for us to extend that into the 3 FDA regulated world in a way that makes sense for us 4 to transfer that regulation. As an independent IRB we 5 don't see as many of those types of studies I think 6 that you might have considered under this particular 7 provision. And there are other independent IRBs in 8 the audience, so I would ask them to provide some 9 feedback as well. But I don't think that the numbers 10 are huge. 11 MS. KORNETSKY: Felix, also, you know 12 we'll get into this that except in the emergency 13 situation, FDA does not -- that's the one part that is 14 different between HHS and FDA regulations is with 15 these criteria of waiver. And we'll have some 16 discussion about that. 17 CHAIRMAN PRENTICE: Ada Sue? 18 MS. SELWITZ: The only thing I would point 19 out, and I thought Felix's point was interesting 20 because I want to commend your Committee and also 21 Susan, since you're part of that Committee as well, 22 because I thought these recommendations were 59 1 excellent, practical, provided excellent guidance for 2 IRBs and for investigators. So I was very pleased. 3 And when I read initially the local norm, 4 that didn't bother me, quite frankly. But in fact I 5 don't think the issue you're raising is limited to 6 independent IRBs. Because I can think at least in my 7 institution several times where we've had protocols 8 that the subject populations were not strictly local, 9 per se. And so I think it's an interesting issue 10 because I know -- I don't think it is that unusual for 11 IRBs independent or academic based to have protocols 12 that have subject populations that cross state lines. 13 DR. FISHER: You know, that's a very good 14 point and maybe the use of the term local is what's 15 throwing us off. Because it could be, you know, 16 perspective participant norms or something like that. 17 I think what we wanted to underscore is that the 18 perspective of parents for whom the permission would 19 be waived was considered. And, you know, I think we 20 might want to change that language instead of local to 21 something like participant norms. And I don't know if 22 that would be helpful. Because you raise a very good 60 1 point. A local IRB may be approving a national study. 2 DR. GYI: Just one more question or point. 3 MS. KORNETSKY: Yes. 4 DR. GYI: Under recommendation three I 5 thought your recommendation was very good to limit the 6 practicability. But I wonder if your Committee had a 7 chance to talk about how we bridge the IRB's 8 understanding of funding related issues and how we get 9 that information to the sponsors themselves, both 10 federal as well as commercial sponsors. But, you 11 know, clearly in this realm it's the federal 12 sponsorship that I'm thinking about. And how do we get 13 those folks to make sure that we are not approving 14 grant applications without appropriate funding. 15 Because if it's going to get stopped at the IRB and 16 how does the IRB know that there's enough money to do 17 the type of things that we're talking about here? I 18 mean, it's funding related, so -- 19 MS. KORNETSKY: That's a tough question, 20 Felix. And I know that in our discussions Dr. Schwetz 21 alluded to the fact that, you know, money is getting 22 tighter and tighter and will continue to get so and 61 1 budgets are cut. You know, it does sometime take a 2 lot of effort and time and money for recruitment. 3 I'm not sure how we can address that. We 4 had discussion, but it's a very thorny issue. 5 DR. FISHER: I think the discussion was 6 that, and this is a tough stance but this was the 7 nature of the discussion, was that if funding agencies 8 are not willing to provide funds that are necessary to 9 protect human subjects, then it's important that they 10 receive that message from IRBs. That IRBs can't be 11 compromised in terms of their responsibility based 12 upon budget cuts. And so I think we did talk about 13 that, and somebody who conducts research and has 14 federal grants and I understand the downside of that 15 completely. But I also understand that that can't 16 compromise the responsibility of the IRB to say that 17 participant have been protected. 18 CHAIRMAN PRENTICE: Yes? All right. Let's 19 get a list here. 20 Okay. Nancy, you're up next and then-- 21 DR. JONES: I don't know if there's any 22 more discussion on this point. I want to move to 62 1 another recommendation. 2 DR. WEINER: Briefly on this point. I 3 think, you know, it's not just cost or speed but it's 4 any expedient measure. Okay. And I think it's 5 important to state that so that, you know, it isn't 6 perceived as an all or none situation. 7 CHAIRMAN PRENTICE: Okay. Nancy? 8 DR. BARRATT: 9 DR. JONES: I was just going to make an 10 additional comment on that point. 11 Peg Barratt from the National Science 12 Foundation. 13 No money goes out the door without having 14 the IRB approval and that documentation in the record. 15 And certainly the appropriate costs for conducting the 16 research are something that we look at. And often we 17 give people less than they ask for, but sometimes we 18 give people more than they asked for because they 19 didn't realize what it was going to cost. 20 Thank you. 21 CHAIRMAN PRENTICE: Okay. Nancy. 22 DR. JONES: My question has to do with the 63 1 next part about waivering guardian permission under 2 46.408. And really you've got to recommendations 3 there. 4 The one part that it seems like you're 5 extending and broadening the phrase about what is a 6 reasonable requirement to protect the subjects. And 7 then they give the two examples of potential harm if 8 disclosure happens. And the part that just jumps out 9 on me is on your recommendation number six that parent 10 permission may not be in the child's best interest. 11 And that's very different than saying presumed to harm 12 in my understanding of that. And it really then seems 13 to me a road at one of the things that the parent does 14 is supposedly act in the child's best interest. And we 15 have to be very careful when the state can waive that 16 role of a parent of acting in the child's best 17 interest. 18 So I don't have any issue with point one 19 or three, but the interpretation when you start going 20 into what is in the child's best interest and whether 21 or not an IRB can basically waive that normal role 22 that a parent has in deciding, is a little different 64 1 than the harm. To me it extends it a little further. 2 DR. FISHER: My understanding, actually of 3 the abuse and neglect was more the child's best 4 interest. There's been many books about this written 5 in the child's interest or not in the child's best 6 interest. And basically it's been defined by that, not 7 so much the harm part. 8 Actually, the abuse and neglect was that 9 if you're going to do a study on abuse and neglect and 10 then the parent is the one who is abusing or 11 neglecting, why would they be giving permission that 12 was not confounded by their own needs? 13 So I think the two is actually the one 14 that-- 15 DR. JONES: But it's used in negligible 16 harm, they're not just a best interest. Like if you-- 17 DR. FISHER: Abuse and neglect are harm. 18 But the example was given because it assumed that 19 parents who abuse their children and then were asked 20 for permission for a child to be in a study about the 21 parental abuse would not be able to make that kind of 22 a judgment. So in actuality that's been something that 65 1 people have been much more focused on for at least 20 2 or 30 years has been what is or is not in the child's 3 best interest. So that has kind of not been the 4 controversial element of it. Although how you define 5 what that is, obviously, is. 6 DR. JONES: Yes. Because for this the one 7 thing that's different when you look in whether or not 8 you're going to give a child medical treatment, that 9 gives a benefit directly to the child and then, you 10 know, you waive parental -- you know, if the parent 11 would choose otherwise or differently. So in research 12 though you know it's not always in the child's best 13 interest to be involved in the research. 14 DR. FISHER: No, of course. But it's also 15 the population interest. So if we go back to the 16 example that we gave of the Al-Anon. Okay. Studying 17 children or you know adolescents who are in Al-Anon 18 because their parents are an alcoholic, one might: 19 (1) that this kind of research will benefit this 20 particular population. That is a conflict of interest 21 for the parent to give permission to have their child 22 in that when it is about -- and in addition, another 66 1 thing about best interest is whether or not the parent 2 is competent at least for that particular situation to 3 give a decision that's in the child's best interest. 4 So it's really the conflict between the 5 topic of the research, whether or not it raises issues 6 that might be outside the child's best interest for 7 the parent to give permission. 8 DR. JONES: I guess, you know, my issue 9 with that, and I can't come up with a quick answer, is 10 also is there a way to use that beyond the boundaries 11 that you've clearly described? 12 MS. KORNETSKY: You're concerned about the 13 harm of using this beyond the boundaries described? 14 DR. JONES: Well, you know really what's 15 happening here is when you think about it is that a 16 research and an IRB get to decide, you know, how to 17 thwart or overcome the normal rights that the parents 18 have to decide for their children. And so I think we 19 have to be careful when we do that. You know, like 20 when you waive. And so it's one thing to say well is 21 there potential harm that's going to occur or threaten 22 a child, you know, if they're in sexual behavior or 67 1 like the Al-Anon use that they're potentially being 2 abused by the alcoholic parents and you want to study 3 that and you want to help them; there is that element 4 of like presumed harm. 5 MS. KORNETSKY: Well, it's not presumed 6 harm. It's that what I think as Celia said again, 7 that a parent would be naturally conflicted and 8 wouldn't necessarily make a decision in the best 9 interests of the child. 10 DR. JONES: Right. 11 DR. FISHER: Remember, one of the things 12 that we tried to address in the beginning of this 13 presentation is that parental permission really 14 addresses autonomy issues with respect to whether or 15 not this is something that it has already been decided 16 by the IRB that the risks and benefits are worth it, 17 there has been sufficient protections against risk at 18 whatever level. And that in fact we're now dealing 19 with and who and how the decision about whether or not 20 the adolescent should participate in the research 21 that's already been decided is appropriate for the 22 population at large. So remember that we're not 68 1 talking about the harm to the child, although 2 obviously an autonomous decision is often based on how 3 it would effect me personally, and that's where you 4 hope that parental permission will have an 5 understanding of the child to understand how that 6 child might be effected. 7 We're not talking about parents' rights in 8 terms of how an individual is affected by the 9 research. We're talking about how the participant 10 would be. And so if the parent cannot help inform 11 about how this might effect the child, him or herself, 12 because of a conflict of aims or whatever, then it's 13 not in the child's best interests to have that parent 14 decide. 15 Remember, the parent could decide to let 16 the child in also, which might not be good for the 17 child. 18 DR. JONES: Right. 19 DR. FISHER: So we're not just talking 20 about exposure to risk that the parent is preventing. 21 It may be that the parent has some self interest, 22 wants to get in good with something, wants to get the 69 1 money for an incentive that's going on. However, what 2 I think you're raising is that you don't want this 3 standard misused. 4 DR. JONES: Right. 5 DR. FISHER: That there's a paternalism, 6 I think, that you're objecting to, which I think is a 7 real one. 8 DR. JONES: Well, if the government or the 9 regulatory or the investigator, the IRB is the one who 10 knows what is in the child's best interest. Because 11 typically we give a lot of latitude that the parents 12 actually make those decisions. It doesn't mean that-- 13 MS. KORNETSKY: Right. Do you think that 14 abuse of a neglectful parents should give consent, 15 give person that we should take out that of 16 regulation? 17 DR. JONES: No. No. No. That's not. 18 MS. KORNETSKY: Okay. 19 DR. JONES: I just feel like this is 20 pushing it slightly beyond the examples that were in 21 the regulations. I'm not saying -- 22 DR. FISHER: Well, there's only two 70 1 examples. And the problem is is that in not having 2 any information, people go -- but what I was trying to 3 say is to try to address your point, because I think 4 we all think paternalism is not what we want. We do 5 not want an IRB or investigators or anybody else 6 making a decision that a parent is not smart enough, 7 doesn't have the appropriate values that we like. 8 That's what we want to avoid. 9 DR. JONES: Yes. 10 DR. FISHER: So it could be, you know, 11 maybe that there's sufficient documentation that this 12 will not be and a rationale for why it would not be in 13 the child's best interest. And basically to 14 articulate that the parent is not able because of 15 either the topic of the research or the status, the 16 kind of status of the parent to make a decision that 17 would reflect how the child might respond to the 18 procedures in saying yes or no. 19 So I understand your hesitation. 20 DR. JONES: Right. 21 DR. FISHER: And I think it's rightly 22 there. But I think we can't get rid of the best 71 1 interest issue because that's how this regulation has 2 been interpreted forever. So we might want to think of 3 a more conservative terminology that could protect 4 against the paternalism. 5 CHAIRMAN PRENTICE: Okay. I have three 6 people on the list. Tom, Amy and Ada Sue. Okay. Tom? 7 MR. ADAMS: I would share some of the same 8 concerns that Nancy just voiced. And I think that it 9 probably goes back to the definition of what study 10 would be in front of us as to what my level of concern 11 might rise. 12 I think if we could define this somewhat 13 more narrowly it would help with that. I'm concerned 14 that we, for example in the alcohol or the abuse 15 examples, I'm concerned that broadly to a class of 16 children we would say that this might even be a 17 problem. What are we trying to find out from the 18 particular study who is going to view the study, how 19 is it going to be used. I think that I would be more 20 comfortable with greater definition here. 21 DR. FISHER: What would you suggest, Tom? 22 What would be the parameters? 72 1 MS. KORNETSKY: What would be the 2 parameters? What would you suggest? 3 MR. ADAMS: That's why I didn't volunteer 4 for this particular subcommittee. 5 DR. WEINER: What would be wrong with 6 instead of trying to mess around with the best 7 interest standard, to try to clarify the circumstances 8 of parental permission that you describe, Celia? That 9 is that there may be a conflict. A conflict of role 10 or a conflict of some -- you know, and we can think 11 about that. But just to put the burden on the first 12 part of that. 13 MS. KORNETSKY: Right. 14 DR. JONES: Another question that is you 15 used in recommendation five the words subject welfare. 16 How is subject welfare the same or different than best 17 interest? Because then you used different words in 18 the recommendation six. Do they mean the same things. 19 DR. FISHER: All right. You know, that's 20 a good point because really that one has to do with 21 harm, the welfare. But then remember we say "or 22 failed to provide additional subject protection. 73 1 DR. JONES: Right. 2 DR. FISHER: That's what addresses the 3 conflict. Okay. 4 Remember, the whole point of parental 5 permission is after an IRB has decided that this is an 6 ethical study, the whole point of informed consent is 7 for someone to decide whether is this something I want 8 to participate in personally. 9 DR. JONES: Right. 10 DR. FISHER: Okay. So the whole point of 11 parental permission is to have a substitute, a 12 surrogate saying whether or not this is something that 13 a child, somebody that does not have the legal 14 competence to consent would want to participate in 15 even though it's ethical. So that the not in the 16 child's best interest is really asking whether or not 17 a parent's opinion will add to the IRB or the 18 investigator knowing whether or not the child would 19 want to -- it's right for the child to participate. 20 Now that doesn't mean, of course, that there's not an 21 independent advocate. Or remember that under this 22 standard there has to be ways of protecting the 74 1 child's autonomy. there is going to be some kind of 2 substitute. 3 You know, I think what Susan Weiner was 4 suggesting that we may want to think about, and I 5 think what both you and Tom are suggesting, in terms 6 of being a little narrower in what we mean is very 7 important. I think the paternalism issue and 8 scientific values overriding parent values is 9 certainly not where we want to go with this. So I 10 think we'll work on some language about that. 11 DR. JONES: Right. Exactly. 12 MS. KORNETSKY: What we'll try and do is 13 what do we mean by child's best interest to flush that 14 out a little bit. 15 CHAIRMAN PRENTICE: Amy? 16 DR. PATTERSON: I'm also commenting on 17 recommendation six. It's the first element, but it's 18 a more semantic issue. Do you really mean to say that 19 informing parents will harm the child or do you mean 20 to say that informing parents may reasonably be 21 expected to result in behaviors or decisions that 22 could harm the child? 75 1 I just have an issue with the statement 2 that says that the mere act of informing a parent is 3 harming the child. I believe that it's the potential 4 actions or decisions or circumstances in the home. 5 There's just a beyond merely informing the parents. 6 MS. KORNETSKY: How about, Amy, informing 7 parents will have potential consequences for harming 8 the child? 9 DR. PATTERSON: I think you all ought to 10 get that working out the wording. But I just wanted 11 another action there that it's not the simple act of 12 telling the parents. It's something downstream 13 emanating from them. 14 CHAIRMAN PRENTICE: That's a good point. 15 The language. As Amy was talking was what I put down 16 was informing parents may result in harm to the child. 17 Would that be -- 18 DR. FISHER: I think we should, and being 19 my conservative, informing -- once again, I also think 20 that the investigators provided sufficient 21 documentation that informing parents could reasonably 22 result in -- might reasonably result in harm to the 76 1 child. 2 CHAIRMAN PRENTICE: Okay. In terms of the 3 discussion about the problems related to best 4 interest, is it possible to come up with some 5 language? 6 MS. KORNETSKY: Yes. 7 CHAIRMAN PRENTICE: Maybe not right now, 8 but during the break so we can -- we don't need a 9 break. 10 DR. FISHER: Well, I certainly think we 11 could. And maybe if Susan or Nancy and Tom, if there 12 are very restrictive terminology that you can think 13 of, I think that there is sufficient documentation for 14 this particular research, the needs of the parents may 15 conflict with the needs or the desires of the child, 16 there's something like that. Because the whole point 17 is whether or not the parents for this particular type 18 of research, not always but for this particular 19 research can make a decision that reflects the self 20 determination rights of the child. Maybe we could 21 think of something. 22 CHAIRMAN PRENTICE: Good. That would be 77 1 good. 2 DR. JONES: So is this always for 3 adolescents? 4 DR. FISHER: No. 5 DR. JONES: See, that's a -- 6 DR. FISHER: But when there's not an 7 adolescent, there has to be a participant advocate. 8 You have to have somebody who is making sure the child 9 is not being coerced. You have to somebody who is 10 making sure the child understands. And that person, 11 the independent advocate is in fact independent that 12 they don't have an investment in the research. That 13 their investment is in the child. 14 MR. ADAMS: Just one additional question. 15 Back over on page 7 when we talk about the child is 16 old enough to give informed and voluntary assent, did 17 I hear you say in discussion that that is generally 18 held to be age 14? 19 DR. FISHER: Yes. That doesn't mean that 20 we should waive parental permission totally. But, 21 yes, the literature demonstrates, many empirical 22 studies, that by somewhere in age 14 or 15 children 78 1 can understand their rights and the elements of 2 informed consent in the same way that adults do. Now, 3 the extent to which they can understand their 4 participation, truly believe that their participation 5 is voluntary is another issue. And that's why that's 6 another element. That it's not just that they 7 understand, but that the investigator has put in 8 procedures that ensure that their participation is 9 voluntary. Because the literature also points out 10 that they may understand that, but given their 11 children and have very little experience with power, 12 that their understanding of their rights to refuse in 13 that situation, especially if they're 14, may not be 14 there. So that's why we have as another protection 15 that they have to demonstrate the protection of 16 voluntariness. 17 MS. KORNETSKY: And I also want to be 18 careful, and I may not agree with Celia on this. I 19 mean, we're not being prescriptive about the age of 20 14. I mean, I think that's what the literature shows. 21 And that's what investigators will need to provide 22 information on. I think a lot will also depend on the 79 1 nature of the research and what's being asked. So I 2 don't think we intended to -- 3 DR. FISHER: Absolutely. 4 MS. KORNETSKY: -- say, you know, 14. 5 This can only apply if the kids are 14 or older. 6 DR. FISHER: Right. And remember our 7 example was social science. If this is a cancer 8 study, you know, I think that we want to look at other 9 things. So I think there is a, as other people have 10 talked about, sliding scale with respect to children's 11 ability to understand the research and waiving 12 parental permission that's a sliding scale with 13 respect to the level of risk. 14 MR. ADAMS: Do we report that sliding 15 scale anywhere? 16 DR. FISHER: We don't. So maybe we 17 should. 18 MR. ADAMS: It just seems to me at the 19 risk of dating myself, and I realize this would be 20 clinical rather than social science, but I can 21 remember about age 12 or 14 participating in a 22 clinical trial for toothpaste, which many of you 80 1 probably may have participated in as well. I don't 2 recall either taking a form home to have my parents 3 sign it or any type of other assent given to 4 participate in the studies. 5 DR. FISHER: Well, if this is in the '60s, 6 that probably true. 7 MR. ADAMS: So you're saying it predates 8 the regulation? 9 CHAIRMAN PRENTICE: There were no IRBs or 10 regulations back in those days, Tom. 11 MR. ADAMS: That's very true. But the 12 point that I make with that is when I was handed the 13 toothbrush and tub of toothpaste it didn't occur to me 14 that I might need to go in and brush my teeth. You 15 know, we went. And so once again I question here when 16 we're talking about something this important not going 17 back and putting in the sliding scale assuming we 18 agree with the sliding scale, which I haven't seen. 19 CHAIRMAN PRENTICE: Ada Sue? 20 MS. SELWITZ: If I'm clear on this, let me 21 remind you in this particular section, though, we are 22 talking about -- it's all within the context of 81 1 minimal research. 2 DR. FISHER: Minimal risk. 3 MS. SELWITZ: And if we look back on our 4 previous report and what has been recommended for 5 minimal risk and how we apply minimal risk, given that 6 standard, I think all of this at least on the 116(d) 7 we have to remember -- 8 DR. FISHER: Right. 9 MS. SELWITZ: -- it's within the context 10 of minimal risk, which is why I can feel more 11 comfortable with the recommendations. 12 DR. FISHER: Right. 13 CHAIRMAN PRENTICE: Would you turn to 14 recommendation seven? When I looked at this 15 particular slide, I wondered whether or not there was 16 a typo. I thought it should have said "when parents, 17 guardians are not present." So are you suggesting a 18 waiver when parent/guardians are available? 19 MS. KORNETSKY: Yes. 20 CHAIRMAN PRENTICE: Okay. I just want to 21 make sure of that. So my understanding is that a 22 child is brought into the ER. They're determined to be 82 1 eligible to participate in a research project that 2 qualifies for the emergency waiver. The parents are 3 available right there, they are in the waiting room or 4 what have you. And that the waiver will apply despite 5 the fact that they are there? 6 DR. FISHER: Right. But remember in the 7 emergency guidelines itself it says the intervention 8 involved in the research must be administered before 9 consent from the subject's legally authorized 10 representatives is feasible. The regulation itself 11 doesn't talk about not feasible because they're not 12 there. It talks about feasible. 13 So you're absolutely right. And once 14 again, this needs to be applied as all emergency 15 waivers do with consideration of all these other 16 parameters which are it's to the direct benefit, 17 there's a life threatening situation; all of those 18 types of situations. 19 The question really is do we want to 20 eliminate emergency research with children that 21 requires immediate action because their parent is 22 there? 83 1 CHAIRMAN PRENTICE: Okay. Now for my 2 second question. In your hypothetical example, which 3 would be -- there you go. You've got two emergency 4 treatments for a life threatening pediatric seizure 5 disorder. And there is clinical equipoise between 6 those two emergency treatments. If it's a randomized 7 clinical trial, one may be approved and one may not be 8 approved, correct? 9 MS. KORNETSKY: I think in this example we 10 were thinking about two recognized approved 11 treatments. 12 CHAIRMAN PRENTICE: Okay. Two recognized 13 approved treatments. And you're coming the efficacy of 14 the two treatments. And then to go back to the 15 requirements for the emergency research waiver, 16 available treatments are unproven or unsatisfactory. 17 So here you have two available recognized "standard 18 treatments," and could you clarify your thinking as to 19 how it meets the requirements that they are unproven 20 or unsatisfactory? 21 DR. FISHER: No. Maybe it's a bad example. 22 Can you? 84 1 MS. KORNETSKY: I mean, I don't think so. 2 I mean I think in emergency situations, you know, 3 there may be something that each of them has adverse 4 effects from it and you're trying to figure out which 5 one has less. So I think there could be things that, 6 you know, that not everything that we do is completely 7 is satisfactory, especially in emergency situations. 8 So it says unproven or unsatisfactory. 9 CHAIRMAN PRENTICE: Okay. 10 MS. KORNETSKY: I would think that this 11 would be probably closer to the unsatisfactory. 12 DR. FISHER: I think what we might want to 13 do is put in a recommendation there that both of them 14 -- you know, something to the extent that neither of 15 them, the elements of which might be more satisfactory 16 -- but, you know, any population, any kind of 17 treatment there are always responder, there always may 18 be ways that -- but I -- would you make a different 19 recommendation than the example? 20 CHAIRMAN PRENTICE: No. I mean it struck 21 me that I was looking at that example and saying okay, 22 you know, how do I apply the criteria for the waiver 85 1 and does it meet the criteria. And I had those 2 questions. And I understand what you're saying, 3 Susan. And those thoughts also occurred to me. But I 4 think that if you're going to give this as an -- 5 DR. FISHER: Right. 6 CHAIRMAN PRENTICE: -- example, I think 7 would be helpful to provide clarification as to how 8 you might meet those requirements. 9 MS. KORNETSKY: Good. 10 CHAIRMAN PRENTICE: Which I don't think is 11 self evident in your example. 12 DR. FISHER: Yes. 13 CHAIRMAN PRENTICE: And also you might 14 consider clarifying, you know as soon as I looked at 15 seven I said there's a typo, it should have said not 16 present. Because that was my mind set. Okay. And 17 clearly that was not what you were thinking. So 18 perhaps you want to clarify that. Because really the 19 waiver applies to both circumstances. Not present or 20 are present, right? 21 DR. FISHER: Yes. Yes. 22 CHAIRMAN PRENTICE: Other questions? 86 1 I would like to be able to come up with 2 satisfactory language. Because we do have another hour 3 and 15 or so minutes and we don't have a great deal 4 more I think to do. So it would be good if we can 5 agree on language for the recommendation. Because we 6 can't agree, there's nothing we can do but send it 7 back to the Subcommittee. All right. So everybody be 8 thinking about what would be satisfactory. 9 DR. FISHER: Ernie, maybe we could -- 10 first of all, we also do have an equally same amount 11 of time for the child dissent. But maybe we could go 12 through those that are unanimous so we know which ones 13 we have to tinker with and which ones not. During 14 that time do you want to take -- 15 CHAIRMAN PRENTICE: Sure. 16 DR. FISHER: -- the group through? 17 CHAIRMAN PRENTICE: Yes. Let's do that. 18 DR. GYI: Just as a point of 19 clarification, do you have a slide for the definition 20 of minimal risk just so we can have a baseline 21 understanding? 22 MS. KORNETSKY: Is there stuff marked 87 1 previous meetings in the book? I hadn't gotten the 2 book beforehand. 3 CHAIRMAN PRENTICE: It's the risk 4 associated with daily life of healthy children living 5 in safe environments. 6 MS. KORNETSKY: Right. 7 CHAIRMAN PRENTICE: Or the risk associated 8 with routine physical medical psychological 9 examinations or tests that are the equivalent of a 10 well child examination. That's basically the thrust 11 of that definition. 12 DR. FISHER: Yes. 13 CHAIRMAN PRENTICE: Did that help? 14 DR. GYI: It does help. I was just 15 wondering that because we have had a lot of discussion 16 around the peripheries of what constitutes acceptable 17 recommendations. But, you know, with the thinking that 18 this is all around minimal risk, by in and large with 19 the exception of that emergency research provision -- 20 MS. KORNETSKY: Not all of it. 21 DR. FISHER: Not all of all. 408 is not. 22 DR. GYI: I'm sorry. You're right. 88 1 DR. FISHER: So that -- 2 DR. GYI: So I was just wondering if we 3 might have that up so that we can remind everybody of 4 what that looks like. 5 CHAIRMAN PRENTICE: Do we have it? We got 6 them all? 7 MS. KORNETSKY: Yes. 8 CHAIRMAN PRENTICE: Okay. 9 MS. KORNETSKY: WE got the old 10 presentations up there as well. So Kelly is going to 11 try and pull that slide up. 12 CHAIRMAN PRENTICE: Phyllis, why don't you 13 have this definition memorized? 14 DR. FISHER: The point is that our minimal 15 -- we'll try to find it. Not the last meeting, but -- 16 DR. GYI: If everybody is comfortable 17 without the definition up there, I'm quite comfortable 18 with that. 19 DR. FISHER: Yes. Remember the definition 20 for children is more conservative so far than what is 21 for adults. So the standard is the healthy child 22 living in safe environments. The normal average 89 1 healthy child, living in safe environments and that 2 the procedures need to be either equivalent to daily 3 life procedures or routine psychological or medical 4 tests. 5 CHAIRMAN PRENTICE: Okay. Right up there. 6 See it. Okay. 7 DR. FISHER: Okay. So I'll just read it 8 into the record. "The definition of minimal risk at 9 45 CFR 46 1020 and applied to Subpart D should be 10 interpreted as those risks encountered by normal 11 average healthy children living in safe environments 12 in daily life or during the performance of routine 13 physical or psychological examinations or tests." 14 All right. 15 CHAIRMAN PRENTICE: All right. Are you 16 ready to go back? 17 DR. FISHER: Yes. 18 CHAIRMAN PRENTICE: All right. 19 Recommendation number one, any problems? 20 MS. KORNETSKY: We're trying to take into 21 consideration the concern about local norms. 22 CHAIRMAN PRENTICE: Yes. 90 1 MS. KORNETSKY: I think we're putting 2 perspective participant norms. 3 DR. FISHER: Well, we could put local 4 and/or perspective participate norms when appropriate. 5 Or do you just want perspective participant norm? 6 Norms of the perspective participant population? 7 CHAIRMAN PRENTICE: I would say that would 8 be the way to go. 9 DR. GYI: Dr. Fisher, if I recall your -- 10 I thought you meant the parents' perspective as 11 opposed to the child's perspective? 12 DR. FISHER: Yes. So how do we say it? 13 MS. KORNETSKY: Well, that's what we're 14 saying. 15 CHAIRMAN PRENTICE: It's -- 16 MS. SELWITZ: Can I make a recommendation? 17 CHAIRMAN PRENTICE: Yes. 18 MS. SELWITZ: You know, I mean these are 19 the kinds of things you think you're fixing and you're 20 trying to do it -- could we put this on their list to 21 look at at the break so at least somebody instead of 22 all of us sitting here trying. You know, just so that 91 1 people can go off and have a little time. So go on -- 2 DR. FISHER: You can have a little time. 3 CHAIRMAN PRENTICE: All right. 4 DR. FISHER: I'm just joking. That's fine. 5 CHAIRMAN PRENTICE: If that's a problem -- 6 yes. You know, it's a good point. When you're 7 talking about local norms, my view is that you're 8 really talking about the norms of the parents as 9 opposed to the kids. 10 DR. FISHER: Right. 11 CHAIRMAN PRENTICE: So we'll put that on 12 hold. 13 DR. FISHER: Okay. 14 CHAIRMAN PRENTICE: Let's go to -- 15 MS. SELWITZ: Not on hold for long. Just 16 on hold -- 17 DR. FISHER: Right. 18 CHAIRMAN PRENTICE: On hold. On hold until 19 after the break. 20 MS. SELWITZ: Okay. 21 CHAIRMAN PRENTICE: Recommendation two, 22 any problems? Okay. All right. 92 1 And I take that, let's kind of go to these 2 recommendations and get them out of the way. 3 All those in favor of accepting 4 recommendation number two as written? Any opposed. 5 Any abstentions? Approved. 6 Recommendation three. Any problems with 7 the language? 8 Yes, Nancy, you want to say something? 9 DR. JONES: I don't know if it's a big 10 thing or not, but the word "dilutes," I know what 11 dilutes mean and then in your example, the example be 12 in there, too. Because then it says what dilute is in 13 a different term. But I would just hate ten years 14 from now somebody would say what did they really mean 15 when they said dilute? 16 DR. FISHER: Weakens. 17 DR. JONES: Weakens might be -- 18 CHAIRMAN PRENTICE: All right. I don't 19 like the word dilute either. 20 DR. FISHER: Okay. 21 CHAIRMAN PRENTICE: Weaken, would weaken 22 be acceptable to everybody? Yes? 93 1 DR. WEINER: Let me just ask you the 2 question that -- 3 MS. KORNETSKY: Yes. What did you say 4 again for that? 5 DR. WEINER: (Off microphone) 6 MS. KORNETSKY: Okay. Good. 7 CHAIRMAN PRENTICE: Okay. 8 DR. GYI: Is there we have spoken about 9 the investigator documenting the requirement? 10 CHAIRMAN PRENTICE: No. No. That's not-- 11 actually, that's not a specific recommendation. 12 MS. KORNETSKY: Let's go back to two. 13 CHAIRMAN PRENTICE: But we can certainly, 14 I think that should be -- 15 DR. FISHER: I think we should insert it 16 in two. 17 CHAIRMAN PRENTICE: It should be inserted 18 someplace. 19 MS. KORNETSKY: It's not only in two, I 20 think it's in all of these. 21 MS. SELWITZ: And I like Susan's approach 22 about using examples and clarifying examples. Because 94 1 I thought the comment you made was exceedingly 2 important both from the standpoint that we need to 3 document that the one thing that can be acceptable is 4 that when the investigator provides the information, 5 that it doesn't have to be in minutes. 6 CHAIRMAN PRENTICE: Right. 7 MS. SELWITZ: And so I think throughout 8 this we could probably get at that issue on how to be 9 documented. I don't think we need a recommendation, 10 but we do need it in an example. 11 CHAIRMAN PRENTICE: Okay. So let's look 12 at recommendation three and then, Felix, we'll go back 13 to your point and then we'll see if we can all agree 14 on -- 15 DR. FISHER: Well, recommendation two, if 16 you look at it, I don't think we need to do that 17 because we're saying the investigators must provide 18 all three criteria. So for that one I don't think we 19 have to have the documentation one. 20 So now for three I don't think this is 21 about the documentation given by the investigator. I 22 think this is judgment of the IRB that there are 95 1 better protections that should be in place and we're 2 not going to accept your proposal simply because you 3 don't have enough money or it's expedient for you to 4 do so. So I don't think documentation goes here. I 5 think we're talking about up the line. 6 CHAIRMAN PRENTICE: All right. So are we 7 agreed on the language in recommendation three? All 8 those in favor? Any opposed? Any abstentions? It's 9 approved. 10 Recommendation four? Any concerns? 11 Hearing none, all those in favor? Any opposed? Any 12 abstentions? Recommendation four approved. 13 I'm assuming that the examples are 14 acceptable. 15 Recommendation five, reasonable 16 requirement? 17 DR. JONES: That's the one that I sort of 18 see linked between five and six. They're in a sense, 19 expanding on the same principle. So I just want to 20 make sure that you may not need two or you may be able 21 to -- 22 DR. FISHER: Yes. We're going to rephrase 96 1 six and see then if we should accept five and six. I 2 think that's a good idea. 3 DR. JONES: Yes. 4 CHAIRMAN PRENTICE: So what are you doing? 5 DR. FISHER: So that one we're not voting 6 on yet. 7 CHAIRMAN PRENTICE: You're going to leave 8 that to the break? 9 DR. FISHER: Yes. 10 CHAIRMAN PRENTICE: Okay. Five and six 11 are the break. 12 DR. FISHER: Yes. 13 MS. SELWITZ: And we're going to have a 14 three day break. 15 DR. FISHER: Seven. Okay. 16 MS. KORNETSKY: So this one I would 17 suggest change to when parents are both present or not 18 present. Is that what you were referring to? 19 CHAIRMAN PRENTICE: Yes. 20 MS. KORNETSKY: Or either, or either. 21 Either. 22 CHAIRMAN PRENTICE: Yes. Yes. That's 97 1 correct. Okay. 2 MR. CORTESI: Well, it should say apply 3 the emergency waiver in an emergency. 4 CHAIRMAN PRENTICE: That's should be self 5 evident, I would hope. 6 Amy? 7 DR. PATTERSON: I have some questions 8 about this and I was wondering if David would chime in 9 here about