1 DEPARTMENT OF HEALTH AND HUMAN SERVICES SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION MEETING TUESDAY, OCTOBER 5, 2004 The Advisory Committee met in the Jefferson Ballroom in the Radisson Hotel Old Town Alexandria, 901 North Fairfax Street, Alexandria, Virginia, at 8:30 a.m., Ernest Prentice, Ph.D., Chairman, presiding. PRESENT: ERNEST PRENTICE, Ph.D. Chair BERNARD A SCHWETZ, D.V.M., Ph.D. Ex. Secretary CATHERINE SLATINSHEK, M.A. Ex. Director THOMAS L. ADAMS, CAE Member MARK BARNES, J.D., L.L.M. Member CELIA B. FISHER, Ph.D. Member ROBERT G. HAUSER, M.D. Member NANCY L. JONES, Ph.D. Member FELIX A. KHIN-MUANG-GYI, Pharm.D. Member SUSAN KORNETSKY, M.P.H. Member MARY L. POLAN, M.D., Ph.D., M.P.H. Member SUSAN L. WEINER, Ph.D. Member EX OFFICIO MEMBERS: HOWARD L. BRADLEY Social Security Admin. KATHRYN LYNN CATES U.S. Department of Veterans Affairs ROGER CORTESI U.S. Environmental Protection Agency HELENE DERAMOND U.S. Dept. of Education SUZANNE GAYNOR U.S. Dept. of Housing & Urban Development DAVID KLURFELD U.S. Dept. of Agriculture DAVID LEPAY, M.D.,Ph.D. Food & Drug Administration AMY PATTERSON National Institutes of Health MICHAEL VIOLA U.S. Dept. of Energy 2 AGENDA ITEM PAGE CALL TO ORDER/OPENING REMARKS: Ernest Prentice . . . . . . . . . . . . . . . . . .3 SUBPART A ISSUES PANEL: Ada Sue Selwitz . . . . . . . . . . . . . . . . . .5 David Forster . . . . . . . . . . . . . . . . . . 21 Daniel Nelson . . . . . . . . . . . . . . . . . . 39 Steve Peckman . . . . . . . . . . . . . . . . . . 58 QUESTIONS FROM SACHRP:. . . . . . . . . . . . . . 86 PUBLIC COMMENTS TO SACHRP: Ivor Pritchard. . . . . . . . . . . . . . . . . .122 Mary Ann Cabo . . . . . . . . . . . . . . . . . .123 John Mather . . . . . . . . . . . . . . . . . . .126 SACHRP MEMBERS DISCUSSION:. . . . . . . . . . . .131 MOTION TO ESTABLISH SUBCOMMITTEE: . . . . . . . .142 AMENDMENT TO MOTION:. . . . . . . . . . . . .144/147 VOTE TO APPROVE SUBCOMMITTEE: . . . . . . . . . .152 DEFINITION OF RESEARCH V. NON-RESEARCH ISSUES PANEL: Michael Carome. . . . . . . . . . . . . . . . . .153 James Hodge . . . . . . . . . . . . . . . . . . .161 Mary Ann Baily. . . . . . . . . . . . . . . . . .185 Peggy O'Kane. . . . . . . . . . . . . . . . . . .203 QUESTIONS FROM SACHRP:. . . . . . . . . . . . . .219 PUBLIC COMMENTS TO SACHRP: Robert Levine . . . . . . . . . . . . . . . . . .250 MODELS OF IRB REVIEW: Michael Carome. . . . . . . . . . . . . . . . . .255 David LePay . . . . . . . . . . . . . . . . . . .259 Susan Kornetsky . . . . . . . . . . . . . . . . .268 Robert Levine . . . . . . . . . . . . . . . . . .280 David Forster . . . . . . . . . . . . . . . . . .293 Lowell Schnipper. . . . . . . . . . . . . . . . .316 DISCUSSION OF COMMITTEE BUSINESS: . . . . . . . .331 MOTION BY COMMITTEE:. . . . . . . . . . . . . . .365 AMENDMENT TO MOTION:. . . . . . . . . . . . . . .367 VOTE TO APPROVE MOTION: . . . . . . . . . . . . .368 ADJOURN: Ernest Prentice . . . . . . . . . . . . . . . . .368 3 1 P-R-O-C-E-E-D-I-N-G-S 2 8:38 a.m. 3 CHAIR PRENTICE: Good morning, everybody. 4 Welcome to the second day of the SACHRP. Welcome 5 Members of the Committee and Members of the Panel. 6 I'm going to briefly overview the agenda for today. 7 I would, however, encourage you to turn off your cell 8 phones. We have a rather in tact program today. 9 We're going to be starting with a Subpart A Issue 10 Panel, Ada Sue Selwitz, David Forster, Daniel Nelson 11 and Steve Peckman, who will go in that order. 12 The way these Panels are going to work, we 13 would like each presenter to come up to, I suppose, 14 here, if you are comfortable. You can change your own 15 slides or we'll get somebody else to change them for 16 you, so you would speak from here and then at the end 17 of the Panel's presentations, all four, we'll have all 18 of you come up and sit up here and respond to 19 questions from SACHRP. 20 I want to encourage everyone to stay on 21 time. You already know the time allocations, 15 22 minutes plus or minus, maybe a minute and a half or 4 1 so. You got that Ada Sue? 2 MS. SELWITZ: Yes, she said I could use 3 20. 4 CHAIR PRENTICE: 20? See, now, you're 5 going to really start a problem here. We're going to 6 have a break after that, then it's public comment 7 period, lunch, and then we go into our second Panel, 8 which is Definition of Research versus Non-Research. 9 There seems to be a lot of confusion these days as to 10 what exactly is research. It's interesting, I'm 11 leaving for Singapore tomorrow and they've asked me to 12 talk about exactly the same thing. They haven't 13 figured out what research is, either, so I guess they 14 are in as bad a shape as we are. 15 Then we will have a break. Then we move 16 into our Panel on Central IRBs at 2:45 to 4:45. Mike 17 Carome, David LePay, Susan Kornetsky, Bob Levine, 18 David Forster and Lowell Schnipper. We'll have a very 19 short period of time for discussion of Committee 20 business and then hopefully we are going to be able to 21 adjourn on time. 22 Now, these are the future SACHRP meeting 5 1 dates. I would encourage you to write those down. We 2 would like to invite you to attend January 31st and 3 February 1st, April 18th and 19th, August 1st and 2nd and 4 November 1st and 2nd in the year 2005. 5 Okay. I think it's time for the first 6 Panel to begin and I'm going to move over to the 7 table. All right. I am going to introduce each 8 speaker, but in the interest of time, I am not going 9 to read their bios. Their bios are available to you 10 and the speakers, I think, are known to almost 11 everyone here. So the first speaker will be Ada Sue 12 Selwitz from the University of Kentucky. Ada Sue, 13 welcome to SACHRP. 14 MS. SELWITZ: Thank you. I'm thrilled to 15 be here. I have to tell you all I was truly honored 16 to be invited to talk to you. I have followed your 17 deliberations. I think what you are doing has the 18 potential to truly strengthen human subjects' 19 protections here in the United States. I think you 20 guys are doing a great job. And I have to tell you I 21 was also really thrilled to be invited, because I was 22 asked to talk about Subpart A. 6 1 You know, honestly, I have sort of grown 2 up professionally with Subpart A. I mean, when I 3 started I was very young. I'm not so young now. I 4 grew up applying Subpart A, and this may sound 5 melodramatic, but it's true, Subpart A has been a part 6 of my life. You know, I don't know about you all, but 7 it's like some family members. There are parts of 8 Subpart A that I love and there are some parts of 9 Subpart A I would really like to change. So I was 10 thrilled to have a chance and my purpose today is to 11 discuss whether 45 CFR Subpart A should be revised, 12 either to strengthen human subjects' protections or to 13 reduce the unnecessary regulatory burden. 14 I want to acknowledge, I talked to lots of 15 people about this presentation. I got lots of ideas 16 from individuals and incorporated some of the ideas 17 into my remarks and I really struggled. I thought how 18 do I do this? How do I in 20 minutes, Ernie, actually 19 -- I did, I talked to Kelly on it, in 20 minutes, how 20 do I layout what I like and what I dislike about 21 Subpart A? And I decided the best way to do it was to 22 do a risk benefit analysis. Okay. 7 1 What are the risks of revision and what 2 are the benefits of revision? So let's talk with the 3 benefits. The benefit is what provisions need to be 4 changed? It's about first on my hit list, the 5 assurance requirement. I'm sure you all are familiar 6 with it, but, essentially, this requirement that we 7 have assigned assurance agreement and what kinds of 8 things need to go in the assurance agreement. 9 Now, if you ask me what do I think about 10 that, based on my years of experience, I don't think 11 it does not strengthen protections. It's an 12 unnecessary regulatory burden. And I think it's 13 especially problematic with those sites that are not 14 legally tied to your institution, but they are engaged 15 in research. This is where the problems I found lie. 16 Let me give you an example of what I'm talking about. 17 We had a researcher that was NIH funded 18 and she was doing research at a variety of non- 19 traditional research sites, including Girl Scout 20 Troops, and if you apply the engagement memo, we had 21 to get assurances throughout this country at places 22 like Girl Scout Troops. But honestly, I'm not 100 8 1 percent sure what the problem is. Okay. I mean, I'm 2 not sure whether the problem is the assurance 3 statement. 4 There is also -- I almost put on my slide 5 that provision 46.113 on cooperative research, because 6 if you look at the FDA version, it doesn't talk about 7 written agreements, but you look at 45 CFR 46, it does 8 talk about written agreements. But I have so much 9 problem with this, that I'm thinking I'm going to have 10 to get a full-time person. A full-time person to 11 manage assurance and other site agreements. And I 12 have to say OHRP, I know you have tried to streamline 13 this process using a variety -- I mean, you really 14 exerted a lot of energy to try to do it. But the 15 truth is it's a problem and it's still a problem that 16 I don't think adds to protection. 17 Next on my hit list continuing review. 18 Now, I think it's important, perhaps, that I explain 19 to you guys where I stand philosophically on 20 continuing review. I really believe if anything we 21 should be doing more at looking at what happens after 22 a protocol is approved. I mean, I think that's where 9 1 we can really strengthen protections. So 2 philosophically, I love continuing review. But from 3 a practical standpoint, I don't think it's working. 4 There is a lot of unnecessary bureaucracy. 5 So I asked myself questions. Do less than 6 minimal risk studies or studies in which no subjects 7 are enrolled need re-review on a yearly basis? I 8 think the answer is no. And so maybe what the problem 9 is is how, if I go back, this is written, but not less 10 than once per year. Because remember, I 11 philosophically support continuing review, but I just 12 don't think it works. There is a lot of paper 13 flowing. 14 Another question is are there more 15 effective models for assessing implementation of 16 approved protocols and I think there are. And maybe 17 in the Q&A we can talk about that, but more than just 18 a yearly review, based on a model where we have to 19 send X kind of material to every IRB member. You 20 know, is the problem 46109(e) or is it interpretation? 21 I want to give you answers today and I don't have 22 answers. I don't know what the problem is, but I do 10 1 think there are more effective ways to strengthen 2 protection through continuing review, and I would like 3 to see continuing review interpreted in a way, so that 4 we could use innovative approaches to try to approach, 5 particularly, for greater the minimal risk protocols. 6 Next on my hit list waiving informed 7 consent. Now, I got to tell you guys, I like the 8 framework and I like we got to have a way to waive 9 informed consent, particularly for social science 10 research. But in terms of applying it over the last 11 too many years, I found some problems. An example, 12 this criterion, you know, you can waive informed 13 consent if an IRB can make a determination that it 14 meets these for criterion. 15 Look at that second criteria. "The rights 16 and welfare of the subject is not adversely affected." 17 Well, it's the word rights that bothers me, because if 18 you have, say, a right as a human subject to give 19 informed consent, then technically I don't see how you 20 could ever waive informed consent. So it's the word 21 rights that I would remove. I think in practice what 22 IRBs really do is they focus on the welfare part of 11 1 this, practicably. 2 You know, I looked at my slides this 3 morning and saw what everybody else is going to say 4 and you're going to hear this again, and I bet if I 5 took each one of you that are on the Committee and 6 took you separately and said okay, Felix, tell me what 7 practicably means. Mary, you tell me what practicably 8 means. If you could even give me an answer, it would 9 probably be different. And so I think there is a 10 problem with this word. 11 On the other hand, I have to tell you 12 truthfully I think in applying this criteria, when you 13 put the word practicably within the context of a 14 research protocol, when you look at a protocol, 15 sometimes it does make sense and it's not as difficult 16 to apply. I mean, really for me, I think the rights 17 is more of a problem than practicably. 18 Next hit list reporting. And again, I'm 19 not sure the problem is this provision, Subpart A. 20 The problem, I think, has to do with the entire 21 system. I know that you are well-aware of it. It has 22 lots to do with other regulations and how they 12 1 interface with this. I won't spend any time on this, 2 because I know that you are already spending a lot of 3 time. 4 Definitions. What are my hit list? What 5 are things I don't like? I can't stand legally 6 authorized representative. I think it's hard to 7 apply. I think it's problematic from the standpoint 8 of state law. I actually think its too stringent in 9 many cases. Human subjects, this is going to be 10 talked about later. I won't spend a lot of time, 11 except living and dead, now, we have HIPAA, right? 12 And, I think, so now we have disharmony between HIPAA 13 and Subpart A. 14 About whom? I think this is going to be 15 talked about later, so I won't spend time here. So 16 maybe I can get it down to 18 minutes. But that I 17 think is a problem. The issue of what is research, 18 you're going to be looking at it. Quite frankly, on 19 what is research? I believe guidance could solve some 20 of those problems, I genuinely do, but I don't go 21 through the day rarely that I don't get a question 22 about is this research? 13 1 Exemption categories, I put them on my hit 2 list, because I think there is a lot of confusion. 3 And I could pick this to death, guys. If we had time 4 today, I could take you through and show you this word 5 and show you that word. So I think there is a lot of 6 confusion about exemptions. In truth though, I think 7 a lot of the confusion can be addressed through 8 guidance. I don't necessarily attribute it to how it 9 is written. I'm not sure my other colleagues will 10 agree with me on that. 11 Another part about exemptions though is 12 from a pure regulatory perspective. I think it would 13 have been good if in the framers of Subpart A they had 14 made as a requirement that it be minimal risk and fit 15 in the categories. I would have liked to have seen 16 that in the regulations. Now, in terms of practice 17 and applying it, I haven't found a real problem with 18 that. I mean, I have not seen exemptions that were 19 approved that were greater than minimal risk. But 20 likewise, if you ask me what would I change, that's 21 one of the items that I would change. 22 Is Subpart A outdated? You know, I hear 14 1 a lot about this. And I sort of agree with it that's 2 why I included it, but Subpart A, we didn't have 3 professional administrators. I remember I went to my 4 first PRIM&R meeting and everybody asked me now, what 5 do you do, are you chair? I said no. Are you the 6 secretary? No. I'm professional staff. And nobody 7 had ever heard of that in 1979. Okay. You know, like 8 there's that part in the reg that the IRB Chair must 9 appoint the expedited reviewers, well, in truth, the 10 IRB professional appoints the expedited reviewers. 11 I hear a lot. I included this last one, 12 because my faculty, my social science faculty would 13 probably shoot me if I didn't say that Subpart A was 14 based on an NIH model and doesn't work as well for 15 social science. But, you know, having said that, and 16 Ernie asked us to talk about where -- I don't blame 17 Subpart A as much as I blame sometimes how IRBs are 18 applying Subpart A, in truth. I think there are ways 19 to apply it in a social science setting, but IRBs 20 simply are afraid or I don't know why they aren't 21 doing it. 22 Okay. Let's switch to risks. One 15 1 analysis is doing this risk benefit assessment. What 2 are the risks of revising Subpart A? What works well 3 in Subpart A? And, you know, I know you can say to me 4 well, Ada Sue, if we revise it, that doesn't mean we 5 will get rid of the good stuff. We'll keep the good 6 stuff. Well, you know, I sort of believe in adages 7 like "be careful what you wish for" or "don't throw 8 out the baby with the bath-water." I heard one 9 recently and I have to write it down. I wish I could 10 tell you who I heard it from, but I don't know. But 11 I can relate to it. "Most problems we face today were 12 created by solutions we implemented yesterday." 13 Okay. And so I think that if we're truly 14 -- if I'm going to lay this out as a risk benefit 15 assessment, you need to think about the risks of 16 opening up Subpart A. So what do I like about it? 17 Well, I have to ask the core question. Would revising 18 Subpart A make ethical decision making more effective? 19 I mean, that's what we're really about, isn't it? 20 Whether it is sound ethical decision making, and my 21 reaction is no, it wouldn't. 22 I think, though, we are all guilty, myself 16 1 included, of always looking to OHRP and IRBs are 2 looking for OHRP and the FDA, we're not going to let 3 the FDA off the hook, and say if you just give us more 4 guidance or if you tell me what this word means, we 5 could do it right. Okay. And so I think there's a 6 tendency for IRBs to look to the regulations for 7 assurances that it's not possible or perhaps even 8 appropriate for regulations to provide. 9 I'm convinced after watching IRBs and 10 Animal Care Committees for over 20 years that it's not 11 possible to eliminate the "grey" associated with sound 12 ethical decision making or to anticipate new questions 13 or ethical challenges that can surface as science 14 progresses. Okay. I'm really convinced of this. You 15 say well, Ada Sue, where are you going? Where is the 16 strength then? What do you like about Subpart A? I 17 really believe it has provided an excellent framework. 18 An excellent framework for ethical decision making. 19 As a matter of fact, I'm amazed at how 20 well it has stood up over time. Truly amazed at how 21 well it stood up over time. And what do I like about 22 it? Some of the very things I told you a minute ago, 17 1 I would change. All right. I like the exemptions. 2 I like the expedited review. I think there is 3 flexibility there without diminishing protections, 4 criteria for approval. The criteria for approval, 5 there's almost a one-on-one match. If I had had time 6 today, I could have illustrated between criteria for 7 approval and the ethical principles. Okay. I think 8 it's excellent. 9 Basic and additional elements of informed 10 consent, yes, I could pick all of these to give. If 11 you give it to me, I can show you words I don't 12 understand and I can show you picky little problems, 13 but overall, I think, it's a great framework, 14 including the fact that we can waive informed consent 15 and documentation of informed consent. I hate the 16 short form. I'm sure some of you all will talk about 17 it. But, you know, overall, I think, it has been an 18 excellent framework that has held up over time. 19 Next issue, let me go back. I better 20 explain this before I say it, because I'm going to 21 make people mad. I really think from a pure 22 regulatory standpoint, pure regulatory here, not human 18 1 subjects' protection, but regulatory, I believe the 2 current system is set up to fail. I think there is so 3 much detail that IRBs and investigators you can't 4 comply. And I hate to say it, but I'm not in the 5 field and I'm telling you there is just so much. And 6 I don't think it's a matter of just how much money my 7 institution puts into my system. There is a point at 8 which there's just so much detail you can't do it any 9 more. 10 Okay. So what does that have to do with 11 why I like Subpart A? Well, I think, Subpart A avoids 12 prescriptive detail and is straightforward compared to 13 many of our other regulations. I mean, I can read 14 Subpart A and understand it. I don't have to hire 15 Mark Barnes, even though he would tell me I should, 16 okay. Actually, we did. 17 MR. BARNES: You need to. 18 MS. SELWITZ: And actually, we did hire 19 Mark Barnes, but to tell me about Subpart A. I liked 20 that it's prescriptive, it's straightforward. I 21 compare it to more recent regulation like HIPAA. You 22 know, this is, I think, a real positive of Subpart A. 19 1 Next issue, one of the most significant 2 regulatory challenges, I think, that face IRBs, and 3 I'm not telling you guys anything you don't know, 4 okay, but one of the most significant is that the 5 research community is the lack of harmony between the 6 federal funding and regulatory agencies with respect 7 to Subpart A and how it is interpreted. Now, I could 8 blame it on Subpart A and I could say well, if it was 9 written different, there wouldn't be any of this lack 10 of harmony. 11 But, you know, I'll be honest with you 12 guys. What I believe is it doesn't matter how it is 13 written. When you have different agencies, you're 14 going to get different interpretations. Okay. I 15 mean, I do. So where am I going with this? What do 16 I think is a prime strength of Subpart A? Subpart A 17 is based on the Common Rule. The Common Rule is the 18 basis of Subpart A. Okay. And I believe that if HHS 19 revises Subpart A that there is no guarantee that the 20 other agencies will revise them accordingly. 21 I think there is just simply no guarantee. 22 And I believe that having uniform regulations provides 20 1 one of the only avenues we have for harmonizing 2 requirements. We maybe are never going to make it, 3 but at least it gives us something, a common uniform 4 set to work off of. I'm afraid that if Subpart A is 5 revised, it could intensify this lack of harmony that 6 we are all struggling with. 7 My final issue, I apologize, this final 8 issue is none of my business. And, in fact, I bet 9 it's not the Committee's business in making your 10 deliberations. But I was on a roll and I couldn't 11 help myself. Okay. And so my final is a practical 12 consideration. There are other parts of 45 CFR that 13 are truly broke and you all have identified those. 14 The work you are doing is fabulous. They need to be 15 fixed and I think any agency has limited resources in 16 correcting. So, I think, if you are going to do a 17 risk benefit analysis, you have to consider, you know, 18 what really needs fixed versus what could perhaps be 19 improved, but doesn't really need to be fixed. 20 So in conclusion, my purpose today was to 21 discuss whether Subpart A should be revised and I 22 tried to address that by outlining for you the risks 21 1 and benefits. Thank you very much. 2 (Applause) 3 CHAIR PRENTICE: Thank you, Ada Sue. You 4 have another 15 seconds. Our next speaker would be 5 David Forster, who is a lawyer and the Assistant Vice 6 President, Office of Compliance at Western IRB, 7 located, as most people know, in Olympia, Washington. 8 Welcome to SACHRP, David. We're looking forward to 9 your presentation. 10 MR. FORSTER: Great. Thank you. And I 11 have way too many slides, so I'm just going to talk 12 really, really fast and go all the way through. I'm 13 going to cover a lot of the same points as Ada Sue, 14 actually, so I can go pretty fast through some of 15 those. But I structured mine a little different. 16 Basic questions, does Subpart A protect subjects? 17 Does it have too much regulatory burden? Those are 18 the questions we were asked. And I just wanted to 19 start off with something this Committee knows very 20 well. It's legislation. 21 Legislation, all legislation suffers from 22 the problem that it's very hard to draft so that it 22 1 applies correctly to all of the cases to which it 2 applies. It's the problem with legislation. So it's 3 not unique to these regs here. It's a problem all 4 through. So do I think Subpart A is broken from a 5 human subject protection standpoint? No. Could it be 6 tweaked? Sure. 7 Do I think there is extra regulatory 8 burden? I have a hard time thinking where to cut 9 back, you know. I see one out of 20 protocols that 10 needs to be stopped, but the rest they just kind of go 11 through and get a bunch of consent form tweaks and, 12 you know, there is regulatory burden there, but I 13 don't know where to cut back on it. And I tried to 14 think should I think outside the box? Do we really 15 need individual review of each protocol? I couldn't 16 get myself away from that either, so I'm kind of stuck 17 within we need something like Subpart A. 18 So what I put as far as the rating scale 19 is do we need to change the regs? I have a couple of 20 those where I think we should, but mostly I think 21 guidance could do it. So I talked to Charlie McCarthy 22 on something else and he said boy, if I was going back 23 1 to look at Subpart A, I would change the exemption 2 criteria. We wrote them in one night, because the 3 Secretary of DHEW rejected them. I had three days 4 before the Carter Administration ended, so in one 5 night we put them under there. 6 They are confusing. The structure is 7 awkward. There is all sorts of unidentified terms and 8 there's this footnote that's a page away that says you 9 can't apply children, prisoners, etcetera in various 10 ones. It's just confusing. Do you need to revise it? 11 You know, we can live with it. Now, that I know that 12 it was written in one night, I think it's really 13 pretty well done, you know. 14 Here is one we do need to change, the 15 definition of LAR. This is a nightmare. It kicks off 16 to state and local law, most state and local law 17 doesn't address it, with a couple of exceptions. OHRP 18 has put out some guidance that's very difficult to 19 interpret. Not guidance, but citation letters. I 20 would like to see a definition put forth in the 21 Federal Regulations that stricter state laws could be 22 held up against, but that would be there for us all to 24 1 rely on. Because right now, I think there is a lot of 2 confusion and there's a lot of legal liability in 3 this. 4 We're going to talk about this later. I'm 5 not going to spend any time on it. The definition of 6 research is difficult. I was kind of playing around 7 trying to come up with a better one. I don't know if 8 I could. I think guidance might be the way to 9 approach that. Another problem with the definition of 10 research, of course, as Ada Sue mentioned, is the 11 different agencies interpret it differently. CDC is 12 just off on a roll with this one, and I kind of get 13 into arguments with them about that. 14 Okay. Definition of human subjects. They 15 came up with -- OHRP really started this idea of 16 secondary subjects when they shot a -- put a shot over 17 the bow at VCU at Mid-Atlantic Twin Registry and then 18 they really haven't said much since and IRBs are 19 incredibly inconsistent on this issue of whether 20 secondary subjects exist at all and what you do with 21 them if you do think they exist. So there's a lot of 22 inconsistency across the country. 25 1 Minimal risk there is lots of discussion 2 on this Panel. The one thing I thought I would 3 mention is I think it needs a better definition. It 4 needs an objective tied down definition. The one 5 thing I hadn't seen in the newspaper reports, etcetera 6 on SACHRP or the various reports is whether you guys 7 had thought about this as a differential risk. And so 8 as I give an example here, to study investigation or 9 new formulation of an approved drug for asthma is 10 minimal risk, because the risk of the intervention is 11 the same as for the approved drug for asthma. 12 I see this reasoning all the time popping 13 up. And here is a classic case, there is this NIH 14 memo out there and some of you may have seen this, 15 this protocol floats around a lot of institutions. 16 It's this drug that's used for intrathecal 17 methotrexate overdose. You have to give it almost 18 immediately. You don't have time for consent. And 19 there's this memo out there from NCI that says the 20 difference is minimal between the risk of an 21 undesirable outcome when standard accepted therapy is 22 used and the risk of undesirable outcome with the 26 1 experimental therapy. 2 Okay. I can use that kind of logic and I 3 can get anything to be minimal risk, right, in way of 4 consent, why not? So I really think that you, as a 5 Committee, when looking at minimal risk should be 6 careful of this differential risk type of argument 7 that is out there. It just comes up in a lot of 8 different formats and it's a hard one to get yourself 9 through in a logical manner. 10 Okay. A very small point. The IRB regs 11 only say that the IRB has the authority to prove or 12 require modifications that are disapproved, but we all 13 have table to defer approval in principle in all these 14 other things. We all use them differently. I think 15 some guidance there might be nice, but it's kind of a 16 small point. 17 Continuing review, like Ada Sue, I 18 wondered do we really need annual continuing review 19 for minimal risk research? And I think maybe not, but 20 I wouldn't want to see that lessened until minimal 21 risk was really tied down as a definition. So it 22 would take a change of the regulations to do it. I'm 27 1 not sure if it's worth cracking open Subpart A for 2 that. 3 Expedited review. There is some 4 regulatory burden created by the fact that the 5 expedited reviewers cannot disapprove research. It 6 has to get kicked up to full board and, you know, that 7 applies to the minor changes in research too, so you 8 have an ad that comes in after research is approved. 9 You can't disapprove it, you have to kick it up to 10 full board. So a simple saying no to an advertisement 11 has to go to full board and it takes a long time to 12 do. I think you could -- that would get rid of some 13 burden and it would take a change to the regulations. 14 Here is an interesting thing, criteria for 15 IRB approval, 111. Here is really what IRBs are 16 supposed to do. This is the kickoff for the ethical 17 decision making. Now, here is the Belmont Report. 18 And where is it? It's after expedited review, right? 19 It's just another little checklist bearing all this 20 procedure stuff and then your substantive material is 21 buried in the middle and it's very short and 22 nondescript. Now, that's both good and bad. And I 28 1 kind of want to bring that point out. 2 First of all, (a)(2) starts off "Risks to 3 subjects are reasonable in relation to anticipate it 4 benefits any of the subjects, and the importance of 5 the knowledge that may be reasonable to be expected to 6 result." Does this require or does this include 7 scientific validity and value to society? I think it 8 does. But there are IRBs out there that have decided 9 it doesn't, and I know that there was a lot of big 10 flap about this recently with the OHRP when they went 11 to look at the ventilator study. 12 A lot of people were saying that they had 13 overstepped, that the IRBs and the OHRP shouldn't be 14 looking at scientific benefit. I don't think you can 15 do a risk benefit analysis without looking at these 16 things. But it's not clear from the regulation that 17 IRBs should. 18 Here is an interesting one. "The IRB 19 should not consider possible long-range effects of 20 applying the knowledge gained in the research." Well, 21 how do we look at things like sex election techniques 22 for embryos? And how about public registries? If the 29 1 IRBs aren't supposed to be looking that far out on how 2 the data is used, well, how far is this boundary that 3 we're not supposed to go beyond? It's in the regs. 4 I don't know where that boundary is. Some guidance 5 would be useful. 6 Here is where I think we have had a lot of 7 discussion yesterday and it's a point that vulnerable 8 subjects is not well-defined. It's confusing and I 9 think there could be a lot of guidance on this to try 10 and clarify. I know my own IRB members get confused 11 all the time. What's vulnerable? And they think that 12 people who can be hurt are vulnerable, rather than 13 thinking of it as a limitation on autonomy. 14 Now, the word vulnerable isn't even in the 15 Belmont Report. It's not in the National Commission 16 thinking, although apparently was underlying it, but, 17 you know, it's not in there. In the Belmont Report 18 they talk about people with limitations on autonomy. 19 So I think it would be nice to tie that back more 20 strongly in the public knowledge. The information is 21 all there. It's just that a lot of people on IRBs 22 don't know that that's the idea of vulnerable, at 30 1 least that's what I believe the idea of vulnerable is. 2 I think guidance is enough here. 3 Defining additional safeguards might be 4 nice. I don't know what they are. I tried to comb 5 over the list once. You get into that problem if you 6 write a list and then something is not on it, you 7 know, it can be additional safeguard stuff issue. So 8 46.111 for me is the crux of Subpart A. It's where 9 the ethical decision making gets its kickoff. It is 10 very broadly written, which is nice, because you can 11 use it very broadly, like the Belmont Report with the 12 principles approach. It's broad. 13 Being broad and non-specific also means 14 that people can fail to use it correctly and you can 15 come up with a pretty skimpy interpretation. That's 16 a strength and weakness. I like the Belmont Report. 17 I think it provides a good framework, but you can 18 misuse the Belmont Report. So I don't know whether we 19 would want to go in and crack the subpart, you know, 20 46.111 and try to make it better. We could make it 21 far worse. 22 Suspension or termination. This is kind 31 1 of a funny thing. Technically, under the regs the IRB 2 only can suspend the research if the research isn't 3 conducted in compliance with the IRB's requirements or 4 there is unexpected serious harm to subject. Well, 5 what if there is just the potential for harm? We do 6 that all the time. We have written our SOP so that we 7 have far more reasons we can suspend or terminate. 8 But quite frankly, I'm always worried some 9 investigator is going to turn around and sue us and 10 say hey, you didn't have the regulatory authority to 11 do that. So I don't know, I wouldn't crack the egg 12 for that one, either. 13 IRB records. This is a tough one. One of 14 the things that came up for us is, for instance, with 15 the minutes. Do you really have to have the basis for 16 requiring changes in our disapproving research in the 17 minutes? Can't it just be over in this -- over here 18 in your computer system? The reason I bring this up 19 is for us, we take our consent forms, we redline them 20 in, and when we make changes we use a legend code. 21 This for regular compliance. This is for state law, 22 etcetera. So we have to -- and we just used to put 32 1 our legend code on our minutes and say that's why we 2 changed our minutes. Not good enough. 3 So now, we put our redline consent forms 4 in our minutes. Luckily our minutes are electronic 5 now, but if you print them out, they are about 400 6 pages, because of all the consent forms attached, or 7 longer. And then, of course, like say under the State 8 of Maryland Law where IRBs have to turn over their 9 minutes, then you have to go through an expurgate all 10 of that stuff in the minutes. It gets to be quite a 11 burden when there are these interpretations that are 12 so rigid as to what the minutes have to contain. It's 13 a difficult issue. 14 This is something that's getting to be a 15 problem for us, just as a record keeping matter, 16 correspondence has to be kept. Email chains, you 17 know, you can get 20 people commenting on some of 18 these things. They go for pages. You have to get it 19 all in your IRB record somehow, and I would just like 20 OHRP to be aware of these electronic record keeping 21 possibilities that are out there and have their 22 guidance keep up with it. I think that a lot of the 33 1 guidance is still very paper-based. So just to be 2 aware that there is a lot of change out there in the 3 record keeping capabilities that exist. 4 Informed consent. You know, people always 5 complain, content there is a process and why do people 6 not pay attention to that? Well, there's only one 7 sentence mentioning the process. The rest all focuses 8 on documentation and the elements. This is a tough 9 one. The part of informed consent regulations, it 10 says you can't waive any rights and the language is a 11 little more complex than that. It very clearly 12 prohibits waivers of negligence. I think it's getting 13 settled on the property rights issue that you can't 14 waive property rights. 15 Here is the one I'm facing now. What 16 about ownership of the intellectual property that 17 results from the research? I think under IP law they 18 probably do own it, the sponsors, Government and 19 private, but there still appears to be a waiver if you 20 put that in there. We're taking it out. So, you 21 know, I'm like Ada Sue, you know, I like their point 22 that maybe more guidance isn't the solution, but I was 34 1 just thinking change the regs or values, so I put 2 guidance down. 3 I thought about should we change this list 4 of the required elements? What could we take out as 5 a regulatory burden? What really doesn't help 6 subjects? You know, the list isn't bad. I could come 7 up with some minor additions, but the IRB already has 8 the right to put those in under the regulations. They 9 can put in additional important information. I 10 couldn't think of anything to take out. I like the 11 elements. 12 Waiver of informed consent. I think all 13 four of us will probably talk about this. Oh, wait, 14 I'm sorry, I jumped ahead. This is one where, this is 15 a waiver of informed consent under 116(c) for state 16 projects where they are looking at various types of 17 benefits programs. You can waive consent for it if 18 it's a state or local Government. But guess what, if 19 it's a federal agency doing it, then it's exempt. 20 Exact same language, right? So I think it's a little 21 hubris from here inside the beltway that somehow the 22 federal agencies are safer and think better of human 35 1 subjects than the state ones. I think we should make 2 it consistent, so that they are both either exempt or 3 you both need IRB review for the waiver of consent. 4 Okay. 116(d), the waiver of informed 5 consent. There are all sorts of problems with this. 6 One is I have highlighted here that "The IRB may 7 approve a consent procedure which does not include or 8 which alters some or all of the elements of informed 9 consent. If, one, the research involves no more than 10 minimal risk." Well, then you can only alter the 11 elements of consent for minimal risk research. 12 Anything above minimal risk you can't alter the 13 elements. 14 Now, there have been, you know, people 15 saying that you can, but five years from when there is 16 all sorts of different people at OHRP and, you know, 17 your compliance always comes when they are looking at 18 something that is three or five years old, you know, 19 just ignoring that black and white reading may get us 20 in trouble. The waiver alteration will not adversely 21 effect the rights and welfare of the subjects, just 22 like Ada Sue was saying. 36 1 What about dignity rights? What about the 2 fact that people don't want their records looked at by 3 other people? And there's a violation if that 4 happens. And, you know, I don't know if you have seen 5 the Research America, there is a poll that comes out 6 once a year, very pro research organization. And one 7 of the questions they ask is assuming there is no way 8 anyone will have access to your identity, would you be 9 willing to release your health information, so that, 10 you know, research can be done? 11 29 percent say no. 29 percent of people 12 don't want their records looked at. But IRBs are 13 waiving consent for records review research all the 14 time. So we kind of tend to put a consequential as 15 harm on this definition instead of a dense logical 16 view. Practicably, I think, Ada Sue did a great job. 17 I don't know what it means. 18 Here is one I do feel really strongly 19 about, just get rid of the short form. The only time 20 the short form pops up is when somebody wants to do 21 consent in the back of an ambulance on stroke or heart 22 attack patients. Then they say, oh, we're going to 37 1 use the short form, you know. We'll get -- you know, 2 that's the only time it comes up. The thing is a 3 nightmare. 4 It's all sorts of extra signing 5 requirements, so I would just get rid of it. And 6 while we're at it, I would get rid of the OHRP 7 guidance on using the short form for non-English 8 speaking subjects. I think it was well-intended at 9 the time, but you can't short change consent to try 10 and satisfy justice. 11 A funny little thing, waiver of 12 documentation of consent. The IRB can waive 13 documentation of consent if it thinks that the main 14 risk of research is a breach of confidentiality 15 occurring because there is a signature on the consent 16 form, right? But then it says at the end, but you 17 have to ask the subject if they want to sign anyway. 18 So imagine this, you're doing an interview at a Needle 19 Exchange Program, you know, in some busy urban center, 20 and you say okay, we want to ask you these questions. 21 We're not going to have you sign a consent. I've 22 described the purpose to you. Now, do you want to 38 1 sign after all, you know? 2 It's just very awkward. It makes, you 3 know, in some of those situations people start to 4 think, as we've had reported to us, that the 5 investigator is really an undercover cop, because all 6 they're saying really is sign it. So I think it's a 7 good idea at times to respect autonomy in that way and 8 the documentation requirements for record keeping, but 9 it's not always a good idea and it's a requirement as 10 the reg is written. 11 And then there's the funding catch-22 that 12 even though just in time funding helped a lot or just 13 in time review, excuse me, there is still this 14 situation that occurs where an investigator wants to 15 finish their research proposal and want to get a grant 16 to do that. They can't get the grant until they get 17 IRB review. They don't have a finished project to 18 give the IRB. And so all the IRBs have this kind of 19 approval and principle or some funny thing we do. 20 But, you know, we always, I always have 21 this problem where I write this letter saying you're 22 approved in principle, but it's not approved, right. 39 1 And then they turn it into the institute and the 2 various institutes of health. Some of them take it, 3 some don't, some call up and say that's not an 4 approval, and so we kind of back off and take out 5 sentences until they say okay, that's an approval, 6 we'll give the grant. But there's hopefully still 7 enough in the letter left to make sure that it looks 8 clear, it's clear to the investigator, they have to 9 bring it back to us. 10 So 20 minutes. Was it close? 11 CHAIR PRENTICE: Only 13. 12 MR. FORSTER: You're kidding. I couldn't 13 do it that fast in my room last night. All right. 14 That's it. 15 (Applause) 16 CHAIR PRENTICE: Thank you, David. All 17 right. Next up is Dan Nelson. Dan Nelson is a social 18 professor of social medicine and pediatrics and 19 Director of the Office of Human Research Ethics at the 20 University of North Carolina Chapel Hill. Welcome, 21 Dan, to SACHRP. 22 MR. NELSON: Thank you. Thank you, Ernie, 40 1 and thank you to the audience and to the Members of 2 SACHRP and I, too, am honored and appreciate the 3 opportunity to talk to you today. My colleagues at 4 UNC, I think, had this mental picture of klieg lights 5 on a Congressional testimony with lots of angry 6 Congressmen facing you across the way and I assured 7 them no, this is a friendly group. I maybe even 8 helped nominate some of them to get on in the first 9 place and we'll just have a discussion among friends, 10 and so remember that when I say something you don't 11 like. But I appreciate the chance to give a critical 12 assessment of Subpart A. 13 The outline is easy. I'm going to split 14 into half general observations on Subpart A as a whole 15 and then some specific problem spots. I often have a 16 problem using too many slides, and so I'm delighted to 17 look at the stack and see that I have fewer slides 18 that any of my colleagues, so I think I can get 19 through this. 20 So beginning with some general 21 observations. The first message, if it ain't broke, 22 don't fix it. And I don't think Subpart A is broke as 41 1 a whole. I think it has served us well for the most 2 part. There are some parts in need of fixing, perhaps 3 in need of guidance and I will get to that in just a 4 second, but I don't think it's in need of total 5 overhaul. Problems where there are, and there are 6 problems, I think, lie more with implementation, 7 application, interpretation and the confusion that 8 comes from misapplication, over-interpretation and 9 poor implementation. 10 Well, if you accept that, then what we 11 really need is a lot of guidance and interpretation 12 from you all as to how to interpret and apply the regs 13 that are vague in parts and purposefully so. So it's 14 great to have this guidance. Indeed, I would say it's 15 critical to have this guidance and much good guidance 16 exists thanks to OHRP and others, but I have to say 17 that it's difficult for the working, the people out in 18 the field to assimilate this and integrate it into 19 their daily practice. 20 And here is an example of that and this is 21 not to slam OHRP. In fact, I could at least find all 22 these in relatively one spot on the OHRP web, but 42 1 there's a lot out there and, again, I think it's 2 difficult to tie all this together. I have talked to 3 people over the last couple of weeks who have been in 4 the field for 20 years and didn't know half of this 5 existed, so you can bet that they are not integrating 6 that into their daily lives and their daily routines 7 in working with IRBs. 8 So a few examples. We have internal memos 9 from division chiefs within OHRP to their own division 10 that may or may not be interpreted by the IRB 11 community as something they should even be looking at 12 or if they can find it and know about it. One of the 13 most useful things out there, engagement of 14 institutions in research, not everybody even knows 15 where that is, even people with a great deal of 16 experience. 17 A lot of dear colleague letters, OPRR 18 reports by the dozens. We have got determination 19 letters to institutions by the hundreds, 20 unfortunately, and great places to learn, but good 21 luck taking those hundreds of letters. And we have 22 staff who love to start their day by reading through 43 1 the latest letters and they learn a lot, but then to 2 take that and put it into the daily practice again is 3 an issue for us. 4 You have actually done some of that hard 5 work by compiling into the OHRP common findings, but 6 again I think to tie all of this together is the point 7 of this slide. I guess, you can find opinions that 8 have been given to individual groups, the Oral History 9 Association being one recent example. The IRB 10 Guidebook was an early attempt to tie some of this 11 together, but I would say as more of an academic 12 exercise than a practical, functional application 13 exercise, but we could debate that later. 14 And there are other things that are just 15 out there that people don't know about unless they 16 happen to have attended a workshop at PRIM&R or happen 17 to get together with you guys on a site visit and work 18 through some of these issues, the Human Subjects 19 Research Decision Charts as an example of that. 20 So again, a lot of good guidance out 21 there, difficult to tie together, and I would say what 22 we would really need is a user's guide to the regs 44 1 that somehow takes your guidance, your 2 interpretations, ties all this together into a 3 working, living, evolving document or source of 4 guidance beyond just the website that is consolidated, 5 updated, integrated, validated and, unfortunately, 6 complicated. I think somehow, and I would be happy to 7 talk about this more during the Q&A period, how can we 8 take all this good guidance that we desperately need, 9 keep it integrated, current and really apply it to our 10 daily routines? 11 Yes, times have changed. I won't say that 12 it's completely out of date. I think it has actually 13 weathered quite well and join Ada Sue in that 14 sentiment, but on the other hand I think we do have 15 what I call single site regulations in a multi-site 16 world. We have regs that were drafted 30 some years 17 ago, 20 at least to govern research that really has 18 evolved and doesn't look like it did 20, 30 years ago. 19 And so we have internal discrepancies, I 20 think, between the importance and relevance that we 21 all give to local review and we need to maintain. 22 There is an internal conflict there with the realities 45 1 and demands of the modern research environment. When 2 we have multi-site trials, we need to be thinking and 3 working more on a common understanding, cooperative 4 review mechanisms. International research has 5 introduced a whole new level of complexity into these 6 cooperative reviews. 7 I'll throw this out just as devil's 8 advocate. Ada Sue already beat me to it, but I have 9 often heard it said that we have inappropriately 10 forced social and behavioral research into a 11 biomedical model. I will throw a shot across the bow 12 and say no, I don't think we have inappropriately 13 forced it in. I think if you look back at the charge 14 of the National and the First Presidential Commission, 15 which had behavioral right in its name, they were told 16 to identify the basic principles, which should 17 underlie the conduct of biomedical and behavioral 18 research, and I think they did a pretty darn good job. 19 I will agree again with Ada Sue that there may well be 20 misapplications, but I don't think it's Subpart A 21 that's at fault for this. 22 Preaching to the choir and the need for 46 1 more education, and OHRP and others have already done 2 a lot of work in this regard. I guess I put this up 3 mainly for the sake of that last item or the last 4 target audience, the funding agencies, and Ada Sue 5 also touched on this. I think if I had just stayed 6 fourth in line, all of these guys would make all my 7 points and I could have made this even shorter, but we 8 haven't compared notes beforehand, so it's going to be 9 interesting to see how this all ties together. 10 I agree, too, there is some discord 11 between the regulatory agencies' interpretations, IRB 12 interpretations and the interpretations of funding 13 agencies. Program officers at NIH are, unfortunately, 14 some of the least informed people I have run into in 15 terms of applying the regs and integrating them and we 16 have many tugs of war not with OHRP or with other IRBs 17 in applying and interpreting, but with funding 18 agencies. 19 So I will close the general observations 20 with a few rhetorical questions. Can compliance and 21 common sense coexist? Is our overemphasis on dotting 22 the Is and crossing the Ts undermining the underlying 47 1 intent of the regs? I like the regs. They are my 2 friend. I guess that's one of the reasons I'm here, 3 but I do fear that we have swung the pendulum so far 4 in the direction of slavish attention to dotting Is 5 and crossing Ts that we're in danger at least of 6 starting to undermine the intent that they are there 7 to serve. 8 Are we forcing institutions to take the 9 easy way out? For example, I hear more and more 10 people talking about limiting their FWA to apply only 11 where federal funding really obligates them to do 12 that, so that they don't have to get caught up in some 13 of the dotting Is and crossing Ts when push may come 14 to shove. 15 So shifting to some specific problem 16 spots, and I will cover these in the order of 17 numerical citation in Subpart A. Exemptions come 18 first, 101. You know the regulatory citation. These 19 are research activities in which the only involvement 20 of human subjects will be in one or more of the 21 following categories. These can be exempt, but I 22 think there is a real catch-22 in the area of 48 1 exemptions. They are technically at least exempt from 2 the policy and that includes IRB review, but of course 3 we all review that to make that determination, so 4 there's a circular argument there, and by the time you 5 make that determination, you're really talking about 6 exempt from continuing review, which is okay. 7 These activities are technically eligible 8 for exemption, yet the issues are still there, the 9 issues we all care about, informed consent, 10 confidentiality, overall protection of subjects, 11 continuing review of amendments that may come up. 12 Well, if you have told somebody to, essentially, go 13 away with an exemption, they may or may not be coming 14 back to you when they are making amendments that may 15 shift it out of an exempt category. 16 I think probably the underlying intent is 17 good. We still exempt several hundred studies a year, 18 so it's not like we have gotten rid of this in our own 19 setting. On the other hand, it creates kind of 20 uncomfortable mishmash, what I would say is an awkward 21 no-man's land somewhere between not human subjects 22 research and what really constitutes expedited review. 49 1 David already touched on this, internal 2 discord. I don't necessarily view it as hubris, but 3 I do see it as a technical discrepancy within the regs 4 themselves at least as I read it. The exemptions cite 5 demonstration projects that are conducted by or are 6 subject to the approval of department or agency heads 7 and I have inserted the word federal there, because 8 that's my understanding of conventional wisdom and I 9 believe that's backed up by OHRP guidance. 10 However, if you look a bit further on, as 11 David already noted, under the waiver of consent 12 criteria, there it specifically states a demonstration 13 project conducted by or subject to the approval of 14 state or local Government officials, and I'm not sure 15 people quite know how to apply that. I'm not sure 16 this is a big ticket item in terms of the work today 17 world. We don't see a lot of demonstration projects, 18 but there is some internal discrepancy there. 19 This is a much bigger deal. You have got 20 a whole Panel this afternoon. I'm glad to see that. 21 The definitions of research, systematic investigation, 22 the application of that and the definition of human 50 1 subject. The problem is, as you well know, that there 2 are many activities that are not quite human subjects 3 research, but carry the same risk for people who are 4 not quite human subjects. We have lots of student 5 projects. 6 It might be interesting to debate at least 7 at a philosophical level the difference between 8 information that is generalizable versus that which 9 will be generalized. You can have a student going out 10 to do the same kind of project that carries the same 11 risk for the person who is not quite a human subject 12 as defined. Why should we be handling that or do we 13 handle it differently than a faculty member who is 14 going to publish that data, therefore, generalizing? 15 You can see where I'm going with that. 16 Studies of organizations. Any unit of 17 interest larger than one individual you can 18 technically rule is not human subjects research. We 19 don't have individual human subjects but, again, we 20 can have the same risks for people involved in that 21 research and the whole area of case studies, an n of 22 1, but the same, certainly, confidentiality issues 51 1 even if not as generalizable as a larger controlled 2 study. 3 I won't spend a lot of time on this. The 4 minimal risk definition, I will just say and I think 5 others have already said it, that many IRBs have 6 trouble applying this. Don't ask me how to fix it, 7 but I can tell you it's a problem in the work today 8 world for IRBs to make this determination fitting in 9 with this current existing definition. 10 This is a much bigger problem, Ada Sue 11 touched on this, the assurance mechanism. I think, 12 again, tying it back to the general observation I have 13 already made about the modern research collaborative 14 environment for multi-site collaborative studies, I 15 think IRBs need guidance and I would say, in fact, 16 encouragement to ask them at least, not to force them, 17 to take a look at ways to share in the review process. 18 I'm not sure that 300 individual IRBs reviewing a 300 19 site study necessarily contributes to the global 20 protection of subjects if that's what we're all about, 21 but yet we all do that. Legal issues, institutional 22 interests force us in that direction. 52 1 I think we need a lot more work and 2 thought and I, again, join Ada Sue in thanking you for 3 the work OHRP has already done toward improving the 4 assurance process, but I think still more needs to be 5 done. The notion of a designated IRB within that FWA, 6 we have simply untenable situations that we're being 7 forced into or guided into in the setting of 8 cooperative, collaborative multi-site studies. IRB 9 Authorization Agreements, unaffiliated investigator 10 agreements. When do you use these? How do you use 11 them? These are all issues. 12 Written procedures. This one is not 13 necessarily a big ticket item, but I will throw it in 14 there just as a small problem spot. The regulations 15 say that we should have written procedures for 16 determining which projects need verification from 17 sources other than investigators that no material 18 changes have occurred since previous review. 19 Perhaps just as the devil's advocate I 20 will ask how often does this really happen? How many 21 IRBs are even aware of this requirement? I view this 22 as kind of one of the trick questions in the regs. If 53 1 you want to ding somebody, go out and survey this 2 audience or go out into the 3,000, 5,000, 10,000 IRBs 3 out there and see how many actually even have the 4 procedures that they need to satisfy the regs, much 5 less are actually applying it. 6 IRB membership, so there's a couple 7 sections in there. 107, as you well know, each IRB 8 shall include at least one member whose primary 9 concern is a nonscientific area and also one who is 10 not otherwise affiliated with the institution. 11 The whole notion of community 12 representation, this has been discussed by many 13 commissions, perhaps by you already, but I would say 14 that the n of 1, that's the latter of the regulation, 15 doesn't necessarily jive with the n of 1 of 5, the 16 notion of a 20 percent representation and I would stay 17 away from setting a percent on that, but I think when 18 IRBs get to have 20, 25, 30 members as many do these 19 days to provide the breadth of expertise, that 20 community voice can tend to get lost and I would urge 21 just to at least be aware of that and I think many 22 IRBs do. Out of our 14 members, we try to have two or 54 1 three who are from outside the institution or a non- 2 scientist, but I don't know that that necessarily 3 translates into a consistent approach across IRBs. 4 This is a favorite whipping boy of ours, 5 convene meeting review in which contingencies are 6 required to go back to a full board. So there are a 7 couple sections that command us to review research at 8 a convened meeting, except when expedited review is 9 used and that we should notify investigators of 10 modifications required to secure IRB approval. There 11 is a problem in returning minor contingencies to a 12 convened meeting. I will give you an example. If the 13 convened group looks at a consent form and says well, 14 the purpose statement is a little too complex, they 15 need to simplify that or clarify that. 16 We have been instructed and advised that 17 we need to have more specific stipulations as to 18 exactly the verbatim language that an IRB would be 19 expecting from investigators. Otherwise, it has to 20 come back to the full board. I will say this as a 21 source of regulatory burden. When you have whole 22 studies and whole consent forms that can be handled 55 1 through expedited review, why is this one needing to 2 go back with IRBs that may be seeing 20 or 30 3 protocols at a meeting to bring back things that truly 4 are minor contingencies, I think, is something I would 5 like to talk about more during the Q&A if we have a 6 chance. 7 Expedited review, I agree with others. In 8 general, I think this works pretty well. There is a 9 small point of confusion in here that I see more and 10 more IRBs at least scratching their heads about. The 11 regulations specify that reviewers may not disapprove 12 the research, but in the next sentence, a research 13 activity may be disapproved only after review in 14 accordance with non-expedited procedures. 15 I see some confusion in applying minor 16 amendments. Does that research or research activity 17 mean the study as a whole that can't be disapproved or 18 if somebody comes up with a hairball amendment to 19 recruit subjects with an ad that the chair can already 20 see needs to be thrown out, can they disapprove that? 21 Does that need to be taken back to the full board, so 22 they can say no, that's a hairball amendment. Let's 56 1 not accept it. That must be a southern phrase, Ada 2 Sue, hairball amendment. I think there is some minor 3 confusion in there, not a big point. 4 Waiver of consent. I like the waiver of 5 consent. We use it every day. I think the practical 6 section is problematic in its application, and I would 7 say that some interpret this waiver as applying only 8 to retrospective reviews. It creates a dilemma where 9 some data exist where you, basically, have a mix of 10 retrospective and prospective data being gathered. 11 They look just identical. 12 I think we're at risk of providing 13 incentive at least for PIs to gain the system in a way 14 or for IRBs to help them gain it. In other words, if 15 you're finding yourself in a situation where you're 16 going to say well, gee, if you were just coming to me 17 a year from now and that data was already on the 18 shelf, I would be waiving this lock, stock and barrel, 19 but now we have got this odd mix of prospective and 20 retrospective, I can waive some, I can't waive the 21 other. I think IRBs can find their way through it, 22 but I think some guidance and thought might be 57 1 helpful. 2 Another element in waiver of consent, 3 whenever appropriate, the subjects will be provided 4 with additional pertinent information after 5 participation. Perhaps turnabout is fair play for the 6 social-behavioral folks. I think this is a behavioral 7 research criterion that was really put in originally 8 to address issues of deception in research or 9 withholding of certain information. I think we often 10 have trouble applying this in the biomedical setting 11 to the retrospective chart reviews, the use of 12 existing specimens. What does it really mean to be 13 coming back to somebody with additional pertinent 14 information? Well, we interpret that and apply it as 15 coming back with clinical information that might be 16 relevant to their individual medical situation. That 17 rarely happens, truth be told. This doesn't 18 necessarily fit. 19 The last slide, and I guess this probably 20 could just as well have been grouped up with the 21 general observations, because I don't know that it 22 ties to a specific citation as much as the overall 58 1 focus, the overall audience for the regulations. I 2 just borrowed this slide from Jeff Cooper who nicely 3 diagramed the sort of patchwork approach that you all 4 recognize. I think we do have some real issues with 5 harmonization across all the different groups and, of 6 course, a whole area of unregulated research. You and 7 others are discussing that and I encourage further 8 looks in that regard. Thank you for your attention. 9 (Applause) 10 CHAIR PRENTICE: Thank you very much, Dan. 11 You may have had the fewest slides, but you had the 12 longest time, but you're still on time, because it was 13 19:30, so thank you for keeping it on schedule. Our 14 next speaker is Steve Peckman and Steve is the 15 Associate Director for Human Subjects Research at the 16 University of California, Los Angeles, UCLA, and I 17 won't go into his bio any further. Welcome to SACHRP, 18 Steve. 19 MR. PECKMAN: Thank you very much for 20 inviting me to speak this morning. I hope to use 21 David's five minutes and Ada Sue's 15 seconds to add 22 on to my time. I was a little shocked to be asked to 59 1 come and speak to this issue just because to discuss 2 whether Subpart A needs modification or not to me at 3 least was a fairly overwhelming task. I haven't been 4 working with Subpart A as long as Ada Sue has, but 5 long enough to know that when I started I didn't have 6 any gray in my beard. 7 I think that Subpart A actually is written 8 really well. Every time I have spoken with Charlie 9 McCarthy about it, like David, I spoke with him about 10 it, I'm impressed at the short amount of time they 11 spent writing it and its enduring quality, and I think 12 what we're going to see this morning and hear this 13 morning is that we all think that flexibility is the 14 key in terms of using Subpart A and probably the most 15 important thing is to -- wow, that was different, is 16 to look at how we can get more guidance in applying 17 Subpart A. 18 So is Subpart A in need of modification? 19 I'm going to talk about the purpose of the regulations 20 as I see it, responsibilities, obligations and 21 institutional culture. I think this is probably going 22 to be the most important part of what I'm going to 60 1 contribute this morning in that we haven't heard 2 anything about the institutional culture and the 3 responsibility of the institution. 4 And in reality, if you read Subpart A very 5 carefully, it describes the responsibilities of two 6 entities, the institution and by extension of the 7 institution, the IRB. Nowhere really in the Subpart 8 A does it explicitly outline the responsibilities of 9 the principal investigator like it does in many 10 aspects of the FDA regulations, and we're not going to 11 pick on FDA this morning, but I hope to attend another 12 meeting where that occurs. 13 Flexibility. The biomedical lens and the 14 ability to define and address all human research. 15 Ernie didn't say this in my introduction, but I'm 16 responsible for three IRBs at UCLA, three biomedical 17 and two social-behavioral. And if I didn't address 18 the issues regarding social-behavioral research, I 19 would be strung up when I returned to Los Angeles. 20 And specifically, I'm the administrator where the 21 rubber meets the administrator at UCLA. And I can 22 tell you that social-behavior researchers, if you 61 1 haven't heard from them already, are really upset 2 about some of the wording in Subpart A and how it 3 inhibits their ability to do research, and I'm going 4 to speak specifically to some of those elements. And 5 then furthermore, how some of the wording and 6 interpretation seems to reflect the biomedical model 7 as you have heard earlier. And then finally, the 8 difference between guidance and regulation. 9 So the purpose of the regulations. Well, 10 the purpose of the regulations, as I see it, is to 11 define in a general outline institutional and IRB 12 responsibilities and obligations. If you read Subpart 13 A carefully, that's all it keeps talking about. So it 14 also talks about the administrative process and 15 documentation requirements. And we have heard a 16 little bit about that, whether these administrative 17 processes and documentation requirements are actually 18 a burden to conducting review of research and the 19 research itself, because the extension of creating a 20 burden on IRB and IRB staff is the biggest concern, is 21 then it delays the implementation of research that is 22 ultimately approved. And actually, in the biomedical 62 1 world, that actually delays the ability of subjects to 2 be accrued just for research and in treatment 3 research, it delays the ability of subject patients to 4 access what wouldn't be normally available treatments. 5 It's a template for addressing ethical 6 issues. The Federal Regulations in Subpart A offer 7 the IRB and the institution a template in which to 8 review research and to address the ethical issues that 9 come before it, and this is where I think the 10 documentation aspects of Subpart A are very important 11 in that what it does is it requires the IRB to step 12 back and say these are the things we must do in order 13 to carry out our obligations as a board that is 14 reviewing the ethics of the conduct of research and if 15 we don't check these off on our list, then we're not 16 actually doing our job. I think that's a pretty sound 17 idea to say let's give them a checklist to review and 18 make sure they document it. 19 And finally, the regulations are a means 20 to an end and not an end in itself, and this has been 21 repeated three times already this morning, which is 22 the regulations are there to help us ensure that 63 1 ethical research is conducted in that manner, and 2 that's why we have the checklist, and though through 3 the OHRP letters that we have heard a bit about this 4 morning, and I will talk a little bit about it as 5 well, we have been instructed on how to use this 6 document as a means to our end. 7 Now, the question becomes whether letters 8 to institutions is an appropriate guidance to the 9 research community and to IRBs as to how to do their 10 job, but ultimately we have to recognize that this is 11 a means to an end to ensure the ethical conduct of 12 research and to ensure the ethical conduct of the 13 institution who is hosting the research. 14 So the responsibilities, obligations and 15 institutional culture, which I feel is the most 16 important part of ensuring an ethical program for the 17 conduct of human research. And this is outlined 18 briefly in a few sections in the document. In 103(a) 19 we talk about the institutional assurance of 20 compliance, which I'm going to go out on a limb this 21 morning as the outlier, I think this is a really 22 important document. This holds the institution's feet 64 1 to the fire. This outlines what the institution's 2 obligations and responsibilities are if they want to 3 be involved in human subjects research. Whether it's 4 an adequate document to that task or not is a 5 different question. 6 103(a) also defines who the institutional 7 officials should be, and I'm going to spend a little 8 bit of time talking about that. 103(b)(2), the 9 responsibility of the institution to support the IRB. 10 And if any of you ever monitor or participate in 11 MCWIRB, now known as the IRB Forum, you will find that 12 at least once a month there are several inquiries 13 about whether there is adequate institutional support 14 of their IRB and what are other institutions doing to 15 support their IRB. 16 And finally, what happens if the 17 institution doesn't discharge its responsibilities 18 effectively? Well, in the little discussed 123 there 19 is an outline of material failure to discharge 20 responsibilities as an institution and what the 21 Federal Government can do to you as a result. 22 So what about these obligations? Without 65 1 an appropriate institutional ethos, regulations and 2 guidance will not successfully protect human subjects 3 period. If the institution that is responsible for 4 the research doesn't have an ethical ethos in how they 5 are going to carry out their charge of responsibility 6 of protection of human subjects, it won't matter how 7 many regulations we have, how much guidance we have 8 and how it's interpreted. It's just not going to 9 happen. 10 So institutional support of the IRB in 11 their decisions builds an ethical institutional 12 culture, and that is what we need to look to in terms 13 of OHRP, in terms of guidance to carry out this charge 14 articulated in 103. What are the agencies' 15 expectations of the institutional official regarding 16 the building of this institutional culture? What is 17 the required definition of an acceptable qualification 18 for an institutional official? Who should that person 19 be in the chain of command? How should they carry out 20 their authority? 21 In 107(e) it describes conflict of 22 interest requirements for IRB members, but there is no 66 1 guidance in the regulation on how conflict of interest 2 requirements should be thought of in terms of an 3 institutional official. Shouldn't the person who is 4 responsible for bringing in, whose sole responsibility 5 at the institution is for bringing in research dollars 6 be the institutional official? If we ask ourselves 7 that question, then we're actually questioning the 8 majority of institutional officials in the country. 9 103(b)(2), institution must constitute an 10 IRB with provisions for meeting space and sufficient 11 support staff to support the IRB's review and record 12 keeping duties. What constitutes sufficient and how 13 should this be assessed? We know from at least one 14 citation letter from OHRP they claim that there was 15 insufficient support of the IRB given by the 16 institution. How was this determined? 300 protocols 17 per staff person? How do you count the protocols? Do 18 adverse events count as a submission? These are the 19 kinds of issues that institutions need as guidance to 20 help them understand what constitutes sufficient 21 support. 22 IRB composition. We have heard a little 67 1 bit about IRB composition. I'm going to spend a 2 little bit more time on this. 46.107 says you have to 3 have a minimum of five members. At most academic 4 medical centers, you will find that their IRBs consist 5 of a lot more than five members, at least one 6 scientist who is an expert in areas of concern, at 7 least one member not affiliated with the institution, 8 at least one non-scientist. So what does this say? 9 IRBs are not obligated to privilege scientists over 10 non-scientists on the IRB. We're going to get to 11 statistics in a minute. Local review and sensitivity 12 to community attitudes are also required by the 13 regulations. 14 So what is the intent of the National 15 Commission? Well, the Commission believes that the 16 rights of subjects should be protected by local review 17 committees operating pursuant to federal regulations 18 and located in institutions where research involving 19 human subjects is conducted. As we have heard 20 already, most of the research now is not conducted at 21 just one institution. It's multi-site institutions in 22 both social-behavioral and biomedical research. 68 1 Compared to the possible alternatives of 2 a regional or national review process, local 3 committees have the advantage of greater familiarity 4 with the actual conditions surrounding the conduct of 5 the research. The National Commission went on to 6 state that you must balance scientific, individual and 7 community concerns on IRBs. You need to guard against 8 scientific self-interest and demonstrate an awareness 9 and appreciation of the various qualities, values and 10 needs of the diverse elements of the community served 11 by the institution, and you have to have a diverse 12 membership. 13 So how does this work out in real life? 14 Well, what's the face of an IRB? The 1995 survey 66 15 percent male, 90 percent white, non-Hispanic. Follow- 16 up survey in '98, little change in the composition of 17 IRB membership, 92 percent white, 58 percent male 18 institutionally affiliated members comprised 83 19 percent of IRB membership. Most non-affiliated 20 members are non-scientists and account for 10 percent 21 of total members. The remainder are institutionally- 22 based non-scientists, such as lawyers, contracting 69 1 grant officers, etcetera. So these are our IRBs that 2 are representing community values. 3 NBAC advised and strongly suggested that 4 IRBs should include members who represent the 5 perspective of the subjects unaffiliated with the 6 institution whose primary concern is in non-scientific 7 areas. It should collectively represent at least 25 8 percent of membership and should be represented at 9 each meeting of the IRB. This way we engage the 10 community of potential subjects. We give the 11 community a voice in the research that is done in this 12 community. And we democratize the process of IRB 13 review. We take it away from the scientific self- 14 interest of the Peer Review Committee and create what 15 was intended for IRBs, which was to be an IRB that 16 would appreciate community values and deliberate on 17 those. 18 So flexibility. I'm going to talk a bit 19 about flexibility. The biomedical lens or the 20 biomedical model and the ability to define and address 21 all human research. So we're going to talk about 22 refining definitions of key elements. We've talked 70 1 about the definition for research, human subject, 2 minimal risk, informed consent, expedited review and 3 I'm going to quickly run through some of these again, 4 because I think I bring a little different spin to 5 them. 6 102(d) research, means a systematic 7 investigation, including research development, testing 8 and evaluation and designed to develop or contribute 9 to generalized knowledge. I hate this definition. I 10 have to say that of all the things in the regulations, 11 this is the most poorly written part of it from my 12 point of view. Because it doesn't make any sense to 13 anyone who read it, who is knowledgeable of the 14 regulations, because what is a systematic 15 investigation? 16 It has never been defined. What is 17 generalizable knowledge? As Dan just said, it's a 18 student researcher whose research may not be intended 19 to be generalized upon initiation, but actually then 20 becomes generalizable knowledge. As the professor 21 says, gosh, you came up with good data. I'm going to 22 use it in my next grant proposal and my next journal 71 1 article. What is generalizable knowledge? Is a case 2 study generalizable knowledge? Why else would you 3 publish it? 4 Yet, it seems to be in the common 5 vernacular that case studies are not under IRB purview 6 nor would anyone want to make case studies under IRB 7 purview. So this is an area where guidance would be 8 very beneficial. 9 Who is a human subject? A living 10 individual about whom? I would pause at the clause 11 about whom is the core of this definition and I have 12 no idea what "about whom" means. The regulations 13 define intervention. They define interaction and 14 private, identifiable information. When is research 15 about a person? Opinions about events external to the 16 person? Is that about the person or are they about 17 the events that are external to the person? 18 Opinions about a work place. If you ask 19 me what it's like to work at UCLA, is that research 20 about me or is it research about UCLA? I won't answer 21 that question by the way. Are objective responses 22 defining who a human subject might be or subjective 72 1 responses? Where do we draw these lines? 2 When does a teacher become a human subject 3 in a school survey study? So you're going to go out 4 and you're going to interview a bunch of teachers and 5 give them a survey. When they answer questions about 6 how many students in the class, what's the average 7 GPA, how many people are tardy per day, how many 8 people miss class, is that about the teacher, is it 9 about the students, is it about the school? Who are 10 the human subjects? Are there any human subjects in 11 that survey? Remember, it's the "about whom" clause 12 that defines whether you have a subject, not the 13 intervention or interaction or the identifiable 14 private information. It's the about whom. 15 Let's say they start to ask how well do 16 your students perform after you do X, Y, Z? If you 17 lecture in the left hand part of the classroom as 18 opposed to the right hand part of the classroom, are 19 the students more responsive? Do they sit more on the 20 right hand side if you lecture to the right hand side 21 of the classroom? Is that about the teacher? Is that 22 about the students? 73 1 Private information. We talked a little 2 bit about this, Virginia Commonwealth was brought up. 3 I'm just going to bring up the questions, in case 4 you're not familiar with the case. I think it's an 5 incredible case. It actually focused IRBs around the 6 country on the about whom clause of the definition of 7 the human subject. Now, whether this was the right 8 case to do it or not, I don't know. And there are a 9 lot of curiosity seekers in the GeneX community who 10 are concerned about this. 11 But these were the questions outlined in 12 the OHRP letter that were asked of the subject about 13 the parents. Is the identifiable information about 14 the adult parent? Is the parent a human subject? 15 Should the IRB be deliberating about the about whom in 16 this case? Again, the Virginia Commonwealth issue is 17 an important one in terms of guidance. This is where 18 guidance is happening through a letter to an 19 institution. The guidance is happening to all 20 institutions rather than through guidance from the 21 agency itself. 22 Exempt from IRB review. What constitutes 74 1 normal educational practice? This drives everyone 2 nuts at my institution. The Department of Education 3 is great, but OHRP needs to collaborate with the 4 Department of Education to come up with definitions. 5 Is randomization among instructional techniques exempt 6 from IRB review? It would appear upon a first glance 7 of the regulation for exemption that it could be. Is 8 it specific to the school of the normal educational 9 practice? The school district? The USA? The globe, 10 we call Earth? 11 What constitutes public behavior in 12 exemption category (b)(2)? What defines publicly 13 available and to whom in category (b)(4)? Assessing 14 risk, physical, social, psychological, economic, there 15 are different types of potential risks and harms that 16 may require different protections. 17 Minimal risk. We determine the level of 18 review. This is a really important definition within 19 the regulations, because it's going to determine 20 everything that the IRB does. If it's minimal risk 21 and fits a certain category, it does through expedited 22 review. If it's more than minimal risk, it goes to 75 1 full committee review. It determines requirements for 2 informed consent and it determines documentation 3 requirements. 4 So probability and magnitude ordinarily 5 encountered in daily life are my two favorite phrases 6 here. We have heard about probability and magnitude, 7 but I'm going to talk about what does "ordinarily 8 encountered" mean? By whom? Whose daily life? I 9 traverse 14 miles every day back and forth across the 10 city of Los Angeles coming and going from work. Is 11 my daily life risk that I daily encounter different 12 than yours? I bet it is for a lot of you. Okay. I 13 go through certain sections of LA that a lot of people 14 probably don't want to go through, and I don't mean 15 Beverly Hills. 16 Informed consent, 117, the documentation 17 requirements. Informed consent shall be documented. 18 A written consent form must be approved by the IRB and 19 signed by the subject and a copy shall be given to the 20 person signing the form, shall be written consent 21 forms signed by the subject. How does a signed 22 document increase protection of the subject? Someone 76 1 needs to answer that question for me sometime during 2 my life working with IRBs. 3 It appears to me it's the protection of 4 the institution and the investigator. Yet, all the 5 other regulations are about the protection of the 6 subject. What is sacred about a signed consent 7 document when such a signature is not required by law? 8 And should there be a difference between social- 9 behavioral and biomedical research in the application 10 and guidance given for 117? Well, this is where we 11 really need some flexibility and guidance for the 12 requirements at home and abroad. 13 Who are our subjects? What are the basic 14 demographic assumptions at home? Who is majority and 15 who is minority in our communities? And here is the 16 case study, California, the place I'm most familiar 17 with, in the 1940s 89.9 percent Euro-American 18 population. David Hayes-Bautista showed in 1992 that 19 we need to question these assumptions, because in 20 California in the 1990, rapid and unoppressive 21 demographic changes challenged our assumptions, 22 because Euro-Americans are now the minority in the 77 1 State of California. 2 Similar trends exist in Texas, New York, 3 Arizona and New Mexico, Florida and Chicago area and 4 changing demographic trends challenge our assumptions 5 of minority versus majority, as well as homogenous 6 Euro-American value systems that may not be applicable 7 to communities of color. In fact, it may intimidate 8 people and force people out of research. So our case 9 study in California, 224 languages spoken in my state. 10 40 percent of the LA County residents are born in 11 another country. This is my home. 12 And the social/political context of 13 signing consent documents is really, really, really 14 different, because people come from communities and 15 cultures where signing documents aren't such a 16 profound noble thing as they are in our Euro-American 17 tradition. So 117 says we can waive signing form 18 consent when it is the only record linking the subject 19 and the research would be -- and the subject and the 20 research would be the consent document and the 21 principal risk would be potential harm resulting from 22 a breach of confidentiality. 78 1 There is flexibility necessary when other 2 methods are available to minimize risk and insure 3 confidentiality. Each subject will be asked whether 4 the subject wants documentation linking the subject 5 with the research and the subject's wishes will 6 govern. If the IRB finds that a signed document may 7 place the subject at risk as the unnoted, why would we 8 want to subject or give them the opportunity to place 9 themselves at risk? 10 If you're going into a crack house to do 11 interviews with crack addicts, you're going to ask 12 them if they want to sign a consent document that 13 identifies them as a crack addict who is being 14 interviewed about crack use? I mean, this just 15 doesn't make any sense. We need to ensure equity and 16 justice with human subjects. We need to recognize the 17 changing demographic and non-western, non-legalistic 18 approach to communication with people who are our 19 subjects. We need to acknowledge international nature 20 of research, both with drug research, device research 21 and social-behavioral research. 22 We need to acknowledge and address the 79 1 historical basis for the negative connotations many 2 people bring to signing documents. And as NBAC noted, 3 flexibility with respect to the documentation process, 4 especially when individuals can easily refuse or 5 discontinue participation would be appropriate. 6 Altering the required elements, you've seen what the 7 requirements are to alter or to waive the requirements 8 for informed consent. 9 So what if you want to do interviews with 10 nomadic people in the Himalayas? They don't have 11 telephones. They don't have electricity. They don't 12 have mail. But yet 116(a)(7) says you have to explain 13 to them who to contact for answers pertinent to 14 questions about the research and research subject's 15 rights and whom to contact in the event of a research 16 related injury of the subject. Does this information 17 have any worth to these people for participating in an 18 interview project about nomadic tribes in the 19 Himalayas? 20 This is the kind of stuff that drives 21 social-behavioral researchers insane. This is the 22 biomedical model that they complain about. This is 80 1 nonsense to people who live in the Himalayas who don't 2 have access to any of the tools that we may have here 3 in the Washington area. Research related injury. I'm 4 going to have to stop for a second and talk about 5 biomedicine. 6 Biomedical research of more than minimal 7 risk. 116(a)(6) says you are required to have an 8 explanation as to whether any compensation is 9 available to the subject should medical injury occur. 10 Now, this allows subjects to participate in more than 11 minimal risk biomedical research at their own risk and 12 relinquishes the sponsor of the institution and the 13 investigator of any responsibility to provide care for 14 injury occurring as a result of research procedures. 15 How are we protecting human subjects here? 16 This is one of the larger loopholes in the 17 regulations. So I could participate in a Phase One 18 trial where the purpose of the study is to find a 19 maximum tolerated dose of a drug, so they're going to 20 keep dosing people until someone gets really sick or 21 dies, and the institution, the sponsor and the 22 investigator can say we're not going to treat you. We 81 1 have no obligation to treat you. You participated in 2 this research at your own risk. 3 Expedited review, I'm just going to talk 4 about minor change. What constitutes a minor change 5 in already approved research? You're doing a Phase 6 One drug trial. 10 subjects have been approved to be 7 enrolled. The 10 subjects did really well. We all 8 have positive responses. You want to add three more 9 subjects to your Phase One trial. Is that a minor 10 change? 11 The short form. A lot has been said about 12 the short form so far. The allowed use of a short 13 form, typically used for non-English speaking subjects 14 in biomedical research. I can assure you that I have 15 not seen anyone use the short form in social- 16 behavioral research. It would be considered 17 incredibly ugly towards the subject to give them a 18 short form with an English translation. Are there 19 safety concerns with the short form? There is no 20 restriction to minimal risk research using the short 21 form. 22 Should we acknowledge the importance of 82 1 justice, but should use be limited to clinical trials 2 with therapeutic intent? Do we want to use a short 3 form for a Phase One trial? Does it promote two 4 classes of research subjects? And this was brought up 5 earlier and alluded to. Does the short form allow us 6 to have non-English speaking subjects who get a short 7 form with a full English language translation of full 8 English language consent document all the risks, 9 alternatives, etcetera and leave these non-English 10 speaking subjects with only a short form with the 11 rules outlined for them? 12 Alternative strategies. We need guidance. 13 Should the short form be limited to screening and 14 initiation of subjects followed by required complete 15 translated inform consent document? Is paper the only 16 acceptable standard? What about guidance for 17 regulations that provide for the use of new 18 methodologies and flexible strategies, such as audio 19 or videotaping the consent process and providing 20 subjects with a copy for reference as their document? 21 I can assure you that even in the most 22 poor sections of LA, everyone has a television set and 83 1 a video-player, but not everyone can read. 2 Suspension or termination of IRB approval. 3 "Grants IRB the authority to suspend or terminate 4 research." Shouldn't IRB have the authority to 5 suspend an investigator? We don't want them to 6 terminate an investigator, of course. But should they 7 be allowed to suspend an investigator? Currently, the 8 regulations don't provide for that. And shouldn't 9 institutional assurance be required to have policies 10 for such an action? 11 You can have a trial where you have 100 12 subjects on the trial. It's a biomedical trial and 13 the investigator has gone way out. But the subjects 14 are doing well. You want us to suspend that research? 15 Who has the authority to remove the investigator? By 16 regulation, not the IRB. 17 Central versus local IRB review. You're 18 going to talk about this this afternoon. 114 talks 19 about cooperative research. Was the intent of 114 to 20 share review among institutions within the same 21 geographic area if we go back to the National 22 Commission idea of what an IRB is or to create central 84 1 IRBs? The central IRB review undermined the local 2 community participation as contemplated by the 3 National Commission and the regulation. 4 Here is my laundry list and now social- 5 behavioral scientific-regulatory expertise in the 6 compliance section of OHRP. This is a necessity not 7 nationwide. Social-behavioral scientists need someone 8 to go to at OHRP who has social-behavioral expertise 9 in the compliance division, so that we can get a 10 guidance that is specific to that type of research 11 without at least the appearance of a biomedical model 12 being used to interpret the regulations. 13 Guidance. Level of detail and written 14 policies and procedures. You've heard about level of 15 detail required for IRB minutes. Level of review for 16 safety reports and adverse event reports. Adverse 17 events, of course, are not even contemplated in 18 Subpart A and standards for scientific review are 19 necessary for guidance. So the efficacy of IRB review 20 is predicated on improved federal guidance, from my 21 point of view. 22 The role of the institution and the 85 1 institutional official responsibility requires more 2 than compliance with the letter of the regulation, as 3 we have already heard. It also requires a willingness 4 to apply the ethical principles that are the spirit of 5 the regulations to create an institutional ethos that 6 governs the actions of all stakeholders and the 7 protection of human subjects. We need more guidance 8 on the composition of IRBs, including the inclusion of 9 community, flexibility of the regulations for specific 10 research paradigms, such as qualitative research. 11 Thank you very much. 12 (Applause) 13 CHAIR PRENTICE: Thank you, Steve. Would 14 the Panelists, please, assemble up at the table? 15 While you are doing that, I'm looking at the schedule. 16 Do we have anybody that's -- okay. I would like to 17 find out whether or not there are individuals here who 18 want to take advantage of the public comment period 19 and address SACHRP? No one has registered. And if no 20 one indicates an indication that they wish to address 21 SACHRP, I'm going to adjust the schedule accordingly. 22 In other words, I'm going to eliminate the public 86 1 comment section. 2 Okay. That will give us more time for 3 discussion. We do have somebody? 4 AUDIENCE MEMBER: Depending on what 5 happens during the question and answer. 6 CHAIR PRENTICE: Okay. Then I'll poll the 7 audience again closer to the break. Then we can 8 decide at that point in time. Okay. I always take 9 the Chair's prerogative of asking the first couple of 10 questions. Many of you had the same concerns, which 11 is, I guess, not surprising. Some of you emphasized 12 concerns to a greater extent than others. One of the 13 things that I found personally to be a real problem in 14 terms of creating what I call uncalled for regulatory 15 burden, and, Dan, you talked about this, and that is 16 when an IRB has reviewed a protocol and they have a 17 series of, let's say, clarifications or modifications 18 to the consent document or the protocol itself, in 19 other words usually it's a request for review form 20 asking more information about the recruitment process 21 or what have you. 22 It's currently the position, as I 87 1 understand it, the position of OHRP that unless the 2 clarification or modification is of a very, very minor 3 nature it has got to be taken back to the full IRB. 4 In consideration of this particular position, we end 5 up at my IRB tabling oh, probably about 40 percent of 6 our protocols, 40 percent. Quite frankly, I don't 7 believe that adds any value to human subjects 8 protection. It simply increases the workload of the 9 IRB members. It delays the initiation of research and 10 I am very comfortable with having the IRB chair or 11 even a subcommittee look at that and say, you know, 12 they responded. We don't need to take this back to 13 the full board. 14 And one of the problems, of course, is 15 that AAHRPP looks at OHRP standards and positions and 16 now, they are going out and looking at what IRBs are 17 doing. So we keep on tabling more and more protocols. 18 It's a catch-22 situation. The more detailed your 19 review, the more likely it is that you're going to 20 have changes, right? The less detailed your review, 21 the less likely it is you're going to have changes. 22 So I consider that to be a big problem, 88 1 but you're really the only one that emphasized that. 2 No one else seemed to have emphasized that and I found 3 that curious. So I guess that would be my first 4 question to the other three where it didn't seem to be 5 a problem at your institutions. Is it not a problem? 6 MS. SELWITZ: I would say that's an 7 excellent point. I think it is a problem. The reason 8 I didn't include it was that I was limited to 20 9 minutes and also, quite frankly, not just the time 10 limit, I was trying to focus on where I thought the 11 problems were perhaps in Subpart A itself. And I 12 don't think that's where the problem is. I think the 13 problem is how Subpart A is being interpreted, and I 14 do think minor should not be interpreted as narrowly. 15 And I think, again, the problem is that 16 the interpretation shifts from time to time given 17 other agencies, David DePay, as well on how it's 18 interpreted in terms of minor. But I agree with you 19 100 percent and I just didn't include it because of 20 time, and I don't think the problem is Subpart A. I 21 think it's the interpretation. 22 CHAIR PRENTICE: I have, obviously, lots 89 1 more questions, but I'm going to open it up for the -- 2 MR. PECKMAN: Could I respond to that one? 3 CHAIR PRENTICE: Yes, sure. 4 MR. PECKMAN: I would agree with Ada Sue 5 that it's not in Subpart A that the problem lies, but 6 in guidance and interpretation. However, it seems to 7 me that some of the guidance that has come out about 8 tabling or deferring proposals is appropriate in that 9 it forces the IRB to really consider what can be 10 approved by a chair, and it forces the IRB then to 11 give very specific information back to an investigator 12 rather than vague guidance saying well, tell us how 13 you're going to do this rather than saying this is 14 what we'll accept as an IRB. And by forcing an IRB 15 into that kind of statement with an investigator, it 16 then grounds the investigator in a place to make 17 decisions and discuss with the IRB how to negotiate 18 the terms of approval. 19 CHAIR PRENTICE: I appreciate that aspect 20 and that is an advantage, but it's also a 21 disadvantage. Okay. We're going to go with our usual 22 routine here. You raise your hands and I recognize 90 1 you and then you ask a question. Susan? 2 MS. KORNETSKY: I just wanted to follow-up 3 on that point, and thank you all for the 4 presentations. The issue that, Ernie, you just 5 brought up is an example where it isn't necessarily 6 the regulations, it's the guidance and this is a 7 catch-22. Yet, throughout everyone's presentations we 8 were saying more and more guidance is needed. 9 So in some respect and, you know, I have 10 been working probably as long as Ada Sue, 20 years, on 11 this stuff and years ago we didn't have to send all 12 that stuff back to the Committee. I don't think any 13 human subject is better protected and I don't know 14 whether I'm correct or not, but I don't even know if 15 there is any guidance on that, but that's something 16 that has come out in determination letters. 17 So in thinking about a lot of the things 18 that you said, the regulations actually give us lots 19 of flexibility. Yet, we're asking for more guidance 20 and when we sometimes get the guidance, then we're 21 sort of cornered in. So I am trying to sort of figure 22 out what the mix is and I don't know the answer and 91 1 you folks don't probably either, but I'm not sure just 2 asking for lots of guidance is the answer. Maybe it's 3 asking for a little more flexibility in being able to 4 interpret things at a local level. I don't know. 5 MR. PECKMAN: Now that I'm awake I can -- 6 I think what you heard this morning was that the 7 document is sound as Subpart A goes, and also that if 8 you ran through everything that we had to say, even 9 though we're each limited to 20 minutes or less, that 10 there is a lot of overlap and there is not a whole lot 11 of areas that need a lot of attention. But there are 12 some very basic and fundamental areas that need a lot 13 of concrete attention, and because there has never 14 been any guidance in these areas, I think is very 15 telling. 16 Fo