1 DEPARTMENT OF HEALTH AND HUMAN SERVICES SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION MEETING MONDAY, AUGUST 1, 2005 The Advisory Committee met in the Jefferson Ballroom in the Radisson Hotel Old Town Alexandria, 901 North Fairfax Street, Alexandria, Virginia, at 8:30 a.m., Ernest Prentice, Ph.D., Chairman, presiding. PRESENT: ERNEST D. 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 NANCY L. JONES, Ph.D. Member FELIX A. KHIN-MUANG-GYI, Pharm.D. Member SUSAN KORNETSKY, M.P.H. Member ADA SUE SELWITZ, M.A. Member SUSAN L. WEINER, Ph.D. Member EX OFFICIO MEMBERS: PEG BARRATT, Ph.D. National Science Foundation HOWARD L. BRADLEY Social Security Admin. KATHRYN LYNN CATES, MD U.S. Dept. of Veterans Affairs ROGER CORTESI U.S. EPA PATTY DECOT U.S. Dept. of Defense HELENE DERAMOND U.S. Dept. of Education SALLY FLANZER, Ph.D. Agency for Healthcare Research and Quality SUZANNE GAYNOR, DrPH, RN, MBA U.S. Dept. of Housing and Urban Development DAVID KLURFELD, Ph.D. U.S. Dept. of Agriculture DAVID LePAY, M.D./Ph.D. Food & Drug Admin. AMY PATTERSON Natl. Institutes of Health 2 LAWRENCE UHTEG NIST MICHAEL VIOLA U.S. Dept. of Energy ALSO PRESENT: KELLEY BOOHER Office of Human Research Protections MICHAEL CAROME Office of Human Research Protections JULIE KANESHIRO Office of Human Research Protections IVOR PRITCHARD Office of Human Research Protections KEVIN PROHASKA Office of Human Research Protections IRENE STITH-COLEMAN Office of Human Research Protections 3 AGENDA ITEM PAGE WELCOME/OPENING REMARKS: Ernest Prentice . . . . . . . . . . . . . . . . . .4 ISSUES REPORT: Bernard Schwetz . . . . . . . . . . . . . . . . . .5 OVERVIEW OF SUBCOMMITTEE CHARGES: Ernest Prentice . . . . . . . . . . . . . . . . . 14 VOTE TO APPROVE APRIL 18TH/19TH MINUTES:. . . . . 16 SUBPART A SUBCOMMITTEE REPORT: Dan Nelson. . . . . . . . . . . . . . . . . . .17/78 Gary Chadwick . . . . . . . . . . . . . . . . . . 27 Moira Keane . . . . . . . . . . . . . . . . . . . 54 QUESTIONS/COMMENTS/DISCUSSION . . . . . . . . . . 97 PUBLIC COMMENT: Alva Schomisch. . . . . . . . . . . . . . . . . .141 Paul Gelsinger. . . . . . . . . . . . . . . . . .147 SUBPART D SUBCOMMITTEE REPORT: Susan Kornetsky . . . . . . . . . . . . . . . . .151 Celia Fisher. . . . . . . . . . . . . . . . . . .162 QUESTIONS/COMMENTS/DISCUSSION . . . . . . . . . .179 405 ISSUES: Celia Fisher. . . . . . . . . . . . . . . . . . .215 QUESTIONS/COMMENTS/DISCUSSION . . . . . . . . . .227 PUBLIC COMMENT: Cami Gearhart . . . . . . . . . . . . . . . . . .260 Rick Herman . . . . . . . . . . . . . . . . . . .262 SUMMARY AND WRAP-UP: Ernest Prentice . . . . . . . . . . . . . . . . .264 ADJOURN: Ernest Prentice . . . . . . . . . . . . . . . . .265 4 1 P-R-O-C-E-E-D-I-N-G-S 2 8:40 a.m. 3 CHAIRMAN PRENTICE: Good morning, 4 everybody. I am Ernie Prentice, the Chair of SACHRP, 5 and I would like to welcome everybody. We will go 6 through our normal introductory comments with regard 7 to the agenda. Once again, I always provide a slide 8 of the SACHRP Charter for those of you who are guests 9 for the first time. This was the charter given to us 10 by Secretary Thompson, September 8, 2004, and you can 11 see that the emphasis of SACHRP is on protection of 12 subjects who are considered vulnerable, such as 13 children, pregnant women, prisoners, decisionally 14 impaired and our work thus far has been focused on 15 vulnerable subject populations. 16 These are the Members of SACHRP and I 17 would like to recognize the efforts of Cathy 18 Slatinshek, the Executive Director, and Kelley. They 19 keep us on time. They get us here. They work very 20 hard to put these programs together and they run so 21 smoothly because of their efforts, so Cathy, Kelley, 22 thank you very much. 5 1 I also want to once again indicate the 2 partnership that SACHRP has with OHRP, in particular, 3 the Director of OHRP, Dr. Schwetz, but also all of the 4 OHRP staff. We work very closely together and this 5 partnership is producing what we think are going to be 6 very important work products that will make a 7 difference. 8 I also want to recognize all the Ex 9 Officio Members of SACHRP, many of whom are here. 10 They work very closely with Dr. Schwetz. They have 11 meetings regularly and issues are identified for 12 discussion and brought to the attention of SACHRP. So 13 that's also a partnership that needs to be recognized. 14 Next, I would like to invite Dr. Schwetz 15 to report on the issues and, Bern, I would assume you 16 are going to do it from there? 17 MR. BARNES: Thank you, Ernie, and good 18 morning to all of you. I have a list of things, a few 19 of which are related to each other, so if there isn't 20 a coherent story, then that is -- you got the gist of 21 it. So I'll start through the list. The Final Rule 22 amending 45 CFR 46 was published on June 13th. It 6 1 includes things that won't change your daily life, but 2 it's tidying up some things that needed to be cleaned 3 up within the Common Rule. 4 For example, changing references to OPRR 5 to OHRP, and revising the footnote at the end of one 6 of the parts of 45 CFR 46 regarding exemptions and 7 subpart (b), and also an update on an OMB Control 8 Number. So this has taken a while to even get these 9 kinds of changes made and signed off on by all of the 10 agencies and departments, who have agreed to the 11 Common Rule, and it gives us some idea of the 12 difficulty of perhaps considering making substantive 13 changes to the Common Rule would not be easy. 14 The next one, OHRP plans to issue for 15 public comment in late August or early September time 16 frame a Draft Guidance Document regarding reporting of 17 adverse events and on anticipated problems involving 18 risks to subjects or others, so that's coming up in 19 late August or early September, and it will be a draft 20 for comments. 21 There are a number of things that have 22 come onto our website that we would bring your 7 1 attention to to get you to go to our website, but also 2 to look for these specific things. At the end of May, 3 OHRP put on its website the guidance on the 45 CFR 4 46.407 process for research involving children. So 5 that is information that came out of the subcommittee 6 that Susan and Celia worked on very early on and 7 SACHRP agreed and approved, so that's now up on our 8 website. And it is the procedure that we have been 9 following during the past year. 10 In May, OHRP posted its guidance on 11 reporting incidents to OHRP. And it is a more 12 definitive guidance on how to report adverse events, 13 changes, things that might affect your IRB, those 14 kinds of things. 15 Another activity that's more under the 16 education heading, during June, OHRP began to pose 17 questions and answers, frequently asked questions 18 starting with questions about assurances, questions 19 about IRB registrations, so it's part of our effort to 20 provide information to people at whatever level of 21 understanding they have that these frequently asked 22 questions with the answer from OHRP is one way for us 8 1 to reach out to provide additional information. 2 One of the discussions that we have been 3 having between the agencies that have signed on to the 4 Common Rule has to do with international research, 5 research in the international community. And what we 6 intended when we started that discussion was to find 7 out agency-by-agency what research are you doing 8 outside the U.S. and are you funding it, are you 9 cooperating as a researcher? What are you doing? 10 What assurances do you have that this is being done in 11 an ethical manner? And what procedures do you have in 12 place in your agency to deal with the surprises that 13 might come up with research done outside the U.S.? 14 So that's an activity that has been going 15 on for some months. One of the things that came up 16 early in that discussion is that it sure would be nice 17 to have a compilation of all of the regulations and 18 guidances that we find across the world. That had not 19 been compiled before. So Ed Bartlett, with the help 20 of others, began that exercise of pulling together all 21 that information. And in July, OHRP posted a 22 compilation of human subject research protection laws, 9 1 regulations and guidelines of over 50 countries where 2 HHS funds are being used to either conduct or to 3 support research. 4 So it is a resource not just for those of 5 us in HHS and not just federal agencies, but for 6 anybody who wants to get onto our website. There is 7 a connection and if you have a specific interest, I've 8 got the website address here. Just see me and I'll be 9 glad to give it to you. But this is a valuable 10 collection of information that will only be useful if 11 people use it. So, please, take advantage of it. 12 Regarding the status of the IRB 13 registration situation, we have received comments 14 after our posting in the Federal Register and we are, 15 at the present time, reviewing the comments within FDA 16 and OHRP to decide how we are going to handle and get 17 ready for the next stage. 18 One of the things that I haven't done in 19 these meetings in the past, and I do at this time to 20 find out if you are interested in having this as part 21 of my report from meeting to meeting, is talk to you 22 about where we are with new compliance cases. OHRP 10 1 receives about 100 complaints per year, complaints of 2 one kind or another, and about half of those result in 3 an investigation of some kind or other. Not 4 necessarily a site visit, but an investigation to look 5 at information. 6 Well, during the past quarter, since the 7 last OHRP meeting, there have been eight new cases and 8 two have closed. And the number of open cases that we 9 have remains around 20, a little above, a little 10 below, so we seem to be at kind of a steady state for 11 the last year or so having about 20 open cases at all 12 times. If this is something that's of interest to 13 you, I'll report it from meeting-to-meeting and if it 14 doesn't take you any place, then I won't bother. 15 Remember, we are funding a committee at 16 the Institute of Medicine that was charged to review 17 the ethics of conducting research involving prisoners. 18 Well, this is a busy committee. They have met several 19 times. They have visited prisons, which we included 20 in there, to give them the perspective of what going 21 to prison, being in the physical setting of a prison, 22 is actually like. So they have done that. And at 11 1 some point in the time when they are ready to come out 2 and comment to us what the status is, we'll be happy 3 to include an update on where they are headed in that 4 committee. 5 Regarding a workshop that SACHRP 6 recommended on alternatives to local IRBs, there was 7 a specific thrust on central IRBs. Let me give you an 8 update on where we are on that. We have a Planning 9 Committee that has developed the charge for this 10 workshop, the agenda for the meeting and a spreadsheet 11 that allows us to compare the pros and cons of all the 12 various models of IRBs that are in use out there, 13 including local IRBs and central IRBs, regional IRBs, 14 other consortia, other ways of doing it. 15 The Planning Committee consists of people 16 from OHRP, from NIH, from the VA, from the Association 17 of American Medical Colleges and American Society of 18 Clinical Oncologists, those two organizations are co- 19 sponsors with us in putting on this workshop. The 20 workshop will be by invitation, so this isn't a 21 workshop that's open to everybody. 22 What we plan is that this workshop will be 12 1 able to come up with recommendations on the various 2 IRB models and when they should be used for various 3 kinds of research, protocols and in certain research 4 sites or communities, whatever the considerations are 5 that would drive you to one form of IRB review process 6 as opposed to another. And the output from this 7 workshop, it will be held on November 17 and 18, will 8 be comments coming back to SACHRP for whatever SACHRP 9 wants to do with those comments. You recommended to 10 us that we would put together such a workshop, which 11 we're doing, and the comments will then come back to 12 SACHRP and you can make specific recommendations or 13 whatever you want from SACHRP. 14 The thing that will follow then will be a 15 conference next year. I mean, if we're having this 16 workshop in November, it won't be until next year 17 before we would have a totally open conference to 18 discuss what came out of the workshop and, at that 19 point, we'll have everybody invited. 20 We can have breakout groups. We can have 21 further discussion about pros and cons or 22 implementation of the recommendations, but I think the 13 1 progress that we have been making on being able to lay 2 out the considerations for making decisions about when 3 you might use a central IRB versus a local or how you 4 manage locally if you use a central IRB, all those are 5 the kinds of issues that we have talked about. 6 So we will bring comments back to SACHRP 7 as soon as we have them from the workshop, and then we 8 will be in the process of planning a larger 9 conference. Ernie, that's my list. 10 CHAIRMAN PRENTICE: Okay. Thank you, 11 Bern. Any questions? Yes? 12 DR. HAUSER: Bern, the adverse event 13 report draft document will be available in this month, 14 and what happens after that in terms of getting to a 15 point where we have some perhaps new recommendations 16 to make? 17 DR. SCHWETZ: Well, we will take all the 18 public comments and make revisions that then undergo 19 further review within HHS and with other federal 20 agencies, and then it would eventually be published in 21 the Federal Register after OMB clearance. 22 DR. HAUSER: How long will that be? Do 14 1 you know? Would you speculate? 2 DR. SCHWETZ: Mike or others, can you give 3 a consideration to the time line? 4 DR. CAROME: Actually, it's not something 5 that will need OMB clearance. 6 DR. SCHWETZ: We don't? Okay. 7 DR. CAROME: So I'll clarify that and we 8 would hope by the end of this calendar year. 9 DR. SCHWETZ: Thanks, Mike, for correcting 10 that. 11 CHAIRMAN PRENTICE: Any other questions? 12 Okay. Great. All right. As usual, we're going to 13 provide an overview of the charges of the SACHRP 14 subcommittees. Currently, we have two subcommittees 15 in operation. Our newest subcommittee is dealing with 16 Subpart A, and I'm sure you all recognize the fact 17 that the regulations for protection of human subjects 18 have remained largely unchanged since 1981. 19 So this is really an exciting subcommittee 20 that's looking at all aspects of Subpart A in order to 21 achieve the goals of enhancing protection of human 22 subjects, reducing regulatory burdens that don't 15 1 contribute to the protection of human subjects and to 2 facilitate ethically appropriate research. It has 3 been a very active subcommittee, as you're going to 4 find out this morning at about 9:00. 5 The second subcommittee we'll hear from 6 this afternoon is dealing with research involving 7 children. That has been in operation ever since 8 SACHRP began, and it has been a very active 9 subcommittee as well. I think they have produced 10 seven reports so far. Is that correct, Susan, seven 11 reports? 12 And Dr. Schwetz indicated that one of 13 those reports have already culminated in 14 recommendations with regard to the 407 review process. 15 We have also had another report that has gone to the 16 secretary of HHS or will do so shortly with regard to 17 other recommendations produced by that subcommittee. 18 The next thing on the agenda is approval 19 of the minutes from our April 18th/19th meeting. Do I 20 have a motion? 21 MR. ADAMS: So move. 22 CHAIRMAN PRENTICE: Second? 16 1 DR. WEINER: Second. 2 CHAIRMAN PRENTICE: Any further 3 discussion? All those in favor? 4 ALL: Aye. 5 CHAIRMAN PRENTICE: Any opposed? Any 6 abstentions? The minutes are approved. 7 Let's go through the meeting agenda today. 8 At 9:00 we're going to have the report of the Subpart 9 A Subcommittee and the co-chairs of that subcommittee 10 are Felix Gyi and Dan Nelson, but they are also going 11 to utilize some of their co-chairs of the working 12 groups to help them present the material and I will 13 allow you to introduce those individuals, Dan. 14 Then at 10:30 we'll take a break. At 15 10:45 we'll continue with the report of the Subpart A 16 Subcommittee. At 12:00 we'll have lunch. From 1:00 17 to 1:30 there will be a public comment period and then 18 we begin our report from the Subcommittee of Research 19 Involving Children and the co-chairs are Celia Fisher 20 and Susan Kornetsky. At 3:00 we'll have a break. 21 We'll continue the report at 3:15. We'll have some 22 time for a summary, a wrap up at 4:15 and then at 5:00 17 1 we will adjourn. 2 So with no further ado, I would like to 3 invite Dan to come up and begin our consideration of 4 the Subpart A. 5 MR. NELSON: Well, thank you, Ernie, and 6 to all of you for the chance to fill you in on what 7 our active subgroup has been up to since you last 8 heard from us. Before I get started, let me just say 9 a personal note of thanks to many of you. 10 You may not tell it from looking, but I'm 11 on vacation right now back in my native midwest, in 12 Iowa and Minnesota, and there was a lot of rearranging 13 and last minute scrambling from Cathy and Kelley and 14 Bern and Ernie and many people in this room to 15 accommodate my travel to get me here and get me back 16 to my family, which I appreciate. So at the same time 17 we certainly are happy to have this opportunity to 18 fill you in on our activities. 19 With me up here are Gary Chadwick and 20 Moira Keane who are co-chairs of our two working 21 groups, and you will hear a lot from them. I'm just 22 going to be the bookends to let them really present 18 1 the meat of our current deliberations. 2 You have just heard the charge of the 3 subcommittee, so I won't spend much time on that, to 4 review and assess all provisions of Subpart A of 45 5 CFR 46 or the Common Rule, as it's often known, 6 relevant OHRP guidance documents and based on that 7 review, an assessment to develop recommendations for 8 consideration by the SACHRP parent committee in three 9 categories in rough order of increasing difficulty, if 10 you will, interpretation of specific Subpart A 11 provisions, development of new or the modification of 12 existing OHRP guidance and, thirdly, possible 13 revisions to Subpart A. 14 Based on the time it took to just work 15 through some relatively small technical corrections, 16 you can imagine that we're approaching that last as a 17 last resort, but I think you'll hear today that we're 18 interested in pushing the envelope with some of our 19 recommendations that may, in fact, lead to possible 20 revision. 21 The goals of that activity are threefold, 22 to enhance protection of human subjects, first and 19 1 foremost and, to accomplish that goal, to reduce 2 regulatory burdens that do not contribute in a 3 meaningful fashion to the protection of human subjects 4 and wrapping those two together, to promote 5 scientifically and ethically valid research. And 6 we'll return to the notion of these intertwining goals 7 and, in particular, the second of those in just a 8 second. 9 The subcommittee membership you have seen 10 before, but let me just quickly run the list, Gary 11 Chadwick up here with me, Bruce Gordon, Ernie's fellow 12 IRB Chair from the University of Nebraska. Felix is 13 a SACHRP Member, Isaac Hopkins, a community 14 representative from New Jersey, Nancy Jones, also a 15 SACHRP Member from Wake Forest, Moira is up here with 16 me, Susan Kornetsky from Boston, a SACHRP Member. 17 Gigi McMillan is the mother of a brain 18 tumor survivor and an active advocate for research and 19 protections in this area. Tom Puglisi is in orange, 20 not to necessarily single him out, but we do want to 21 do that both to thank Tom for his activities thus far 22 and to comment that, going ahead, Tom has chosen to 20 1 return from the private sector to Government service 2 with the VA, and we have certainly appreciated his 3 input to the subcommittee thus far and are working on 4 ways to keep him involved. 5 Now that he is a federal servant, that 6 will change his membership on this subcommittee, but 7 we're very anxious and grateful for Tom's continuing 8 input to our activities. Lorna Rhodes from the 9 University of Washington, an anthropologist, Ada Sue 10 is on SACHRP and not here just at this second, and 11 David Strauss from the New York State Psychiatric 12 Institute. 13 We have held four meetings with the 14 subcommittee as a whole dating back to last January, 15 had two on-site meetings here in Alexandria and 16 interspersed in supplementing those group meetings are 17 too many working group calls and conferences and 18 meetings to count and, really, that's where a lot of 19 the work has come from that you're going to hear about 20 shortly and I think a testament to, I guess, the 21 modern telecommunications environment, but also the 22 hard work of these folks up here and our subcommittee 21 1 members to be able to pull together what you're going 2 to hear about largely long distance where we're 3 realizing that nothing can replace an in person 4 meeting to really be able to build consensus and 5 debate on some of these issues, but they have 6 accomplished a great deal long distance. 7 At our first meeting, we developed a 8 laundry list, if you will, of topics for consideration 9 by this subcommittee and this is the list. The first 10 two you're going to hear about today, continuing 11 review and expedited review, and those were the two 12 broad categories of issues that filtered to the top as 13 our first priorities to tackle. 14 Also on the list for possible 15 consideration, however, are assurances, what it means 16 to be engaged in research, how should assurances be 17 handled for off-site research in nontraditional 18 settings, such as schools for example. Multi-site 19 research, we have heard about the AAMC-OHRP Workshop 20 that is coming up looking at this and examining 21 various models for handling what I think we all would 22 recognize as a difficult and complex area. 22 1 Record keeping and reporting. 2 Investigator responsibilities is something that we 3 keep returning to as perhaps in need of some focused 4 attention as one of the other stakeholders and one of 5 the parties who shares responsibility in this process 6 of protecting subjects. Informed consent, obviously, 7 a big topic, not only waivers, but all the elements of 8 informed consent and you will hear that that is now 9 lining up in the queue as one of our next topics for 10 consideration, as is exemptions. 11 IRB review of exceptions and deviations, 12 protections for vulnerable populations and 13 definitions, which are woven throughout, and you will 14 hear a fair amount about our thoughts about minimal 15 risk, which is one of the intrinsic and pivotal 16 definitions in Subpart A. 17 We have noted that, not on the list, as a 18 discreet topic is adverse event reporting, not because 19 this is not important, but because there is a federal 20 working group under Amy Patterson's lead looking at 21 this. Even still, we have commented on adverse event 22 reporting in the specific context of continuing review 23 1 and expedited review, and you will hear about that, 2 but we didn't want to set that aside as a separate 3 topic that this subcommittee would do, but rather our 4 waiting with baited breath to see what the Federal 5 Working Group comes up with. 6 We established several criteria for 7 prioritizing from that long list. Ernie and others 8 have noted that's a lifetime's work and we're trying 9 to figure out what we can realistically chew on and 10 come up with recommendations on in a reasonable time 11 frame. The importance of the problem, the relative 12 ease of addressing or fixing the problem, again, 13 interpretation being somewhat easier to address the 14 guidance than revision of the regulations, the effect 15 on human research protections and the contribution to 16 regulatory burden and non-regulatory burden. 17 So applying those criteria, these two, 18 again, topics came out as to where we focused our 19 attention first. Gary Chadwick and David Strauss are 20 co-chairs of the Working Group on Continuing Review 21 and Tom Puglisi and Moira Keane are co-chairs of the 22 Working Group on Expedited Review. Again, a great 24 1 deal of hard work has come out and in relatively short 2 time from these groups and we're very grateful for 3 that. 4 Many of you are familiar with this cartoon 5 from Sid Harris, in the midst of complex scribblings 6 then a miracle occurs, and I guess this could be Felix 7 and I. Considering the works of our two working 8 groups, I think it has been close to miraculous what 9 they have managed to accomplish in relatively short 10 order. We're anxious to turn the podium over to them 11 in just a second and let you hear directly from them. 12 Our second on-site meeting was held just 13 a week or so, a week and a half ago, in Alexandria, I 14 guess in this very hotel, and Volume II of an 15 ambitious agenda, noting that our first meeting also 16 was quite ambitious in what we hope to accomplish and 17 I think we did that again with this day and a half 18 meeting. We reviewed the draft reports on expedited 19 review and continuing review, had a lengthy discussion 20 on minimal risk and gained input from our ex officio 21 federal agency representatives, many of them in this 22 room today, on all of the above. 25 1 What we would like to do for the rest of 2 the day then is share our thoughts coming out of that 3 meeting, and I will first just set a few ground rules 4 and caveats for this discussion. We would ask you to 5 bear in mind that our first opportunity as a 6 subcommittee to really review and work toward 7 consensus on these complicated issues was just a short 8 time ago, July 20th and 21st. 9 We have come a long way in our thinking. 10 Many of the recommendations are, I would say, 11 penultimate versions, but none of these are quite 12 ready for unveiling as our final recommendations to 13 SACHRP and to the rest of the world. But 14 nevertheless, we wanted to share our preliminary 15 thinking toward these recommendations and, based on 16 your input and our further thinking within the 17 subcommittee, would then put forth final 18 recommendations in relatively short order. 19 I think with another month rather than 20 just a week in between times, we might have come back 21 with something a bit more final that we were ready to 22 endorse and release as such, but we did want to take 26 1 this important opportunity today to get SACHRP 2 feedback and audience feedback, public feedback. It's 3 very welcome. 4 It's neither too early nor too late in the 5 process for us to factor this into our thinking, and 6 we're not close to the notion that we may have missed 7 some issues. As broad and out of the box as we tried 8 to think, there may well be additional issues and we 9 would welcome you to bring those to our attention 10 today or thereafter. 11 A final caveat on an issue that I think 12 many who work daily in the IRB world may take for 13 granted, but not everybody necessarily does, is that 14 regulatory burden reduction may stand the risk of 15 being confused with work reduction, and we would ask 16 you to bear in mind that that's not the case. That's 17 not the goal. 18 There are requirements or interpretations 19 that don't add meaningfully, we would argue, to the 20 protection of human subjects and it's clear to us, 21 again, who spend our time working in this area that in 22 an area of limited resources and limited time and 27 1 limited staffing that every minute of the day spent on 2 issues that don't contribute meaningfully actually 3 detract actively from the meaningful protections, 4 where the real meat of human subjects protections are. 5 And so as you hear these things, please, bear that in 6 mind as we certainly do in coming forth with these 7 thoughts. 8 With that, I'm going to turn it over to 9 Gary Chadwick. I guess this is again maybe Felix and 10 I cracking the whip on the working groups, but really 11 the working group co-chairs have done the heavy 12 lifting in this process. And we wanted you to hear 13 directly from them, those who have thought most 14 directly on this and also to give credit where credit 15 is due, because they deserve a great deal in this 16 process. 17 DR. CHADWICK: Thank you, Dan and Felix. 18 As I was coming up, Felix reminded me that we only 19 have three hours to cover this, so I think he is well- 20 aware of my propensity to be a wanderer, both 21 physically and mentally. So in the interest of 22 staying on time, I'm going to, and staying on topic, 28 1 actually try and read more or less prepared remarks 2 today. Not my usual style, but I think you'll all be 3 the beneficiaries. 4 First of all, of course, I want to thank 5 my co-chair, David Strauss, and all the members of the 6 working group. As Dan said, we did put in some long 7 hours and many telephone calls, many emails and I know 8 lots of work on weekends that would have been 9 otherwise spent in more pleasurable pursuits perhaps. 10 As I say, the work group has come up with lots of 11 material, so we'll get at it. 12 Let's see, which button do I hit here? 13 This one? Okay. The regulations grew from the 14 Syphilis Study and one major concern about that study 15 was that it went for years, decades really, without 16 scientific or ethical review. Continuing review of 17 research was intended to prevent ongoing research 18 activities in the face of unacceptable harm, utility 19 or technological or ethical obsolescence. 20 It is interesting to note that the Belmont 21 Report does not mention continuing review as one of 22 the suggested applications, which they did make 29 1 suggestions toward application, and they did not 2 mention continuing review. As Dan pointed out, we 3 started out with some working assumptions in both the 4 work groups and the subcommittee. We all felt very 5 strongly that continuing review plays a central, often 6 understated, role in the IRB process. We tend to 7 focus a lot on the initial review, but I believe, we 8 all do, that continuing review is an important tool, 9 but it must be used correctly. 10 As Dan noted, any practices that do not 11 promote demonstrable safety and ethical practice in 12 research diminish overall human subject protection. 13 It's a resource allocation issue. There is only so 14 much an IRB can do. 15 Two main questions for this group, as I 16 imagine for others, will be what do the regulations 17 require? What is the letter of the regulations? And 18 what is the intent of the regulations? What is the 19 spirit behind the letter? The spirit has always been 20 to adequately protect human subjects without 21 unnecessarily hindering research. These two 22 conditions imply some sort of balance. The letter has 30 1 been to set a floor or a direction with few absolutes. 2 The term continuing review is used six 3 times in Subpart A. That seems like a lot, but all 4 but one of those references are concerned with 5 requirements other than the definition of the term 6 and/or the procedure itself. So we find it in 7 sections on assurance requirements, IRB Member voting 8 and records. Only Section 109 addresses the 9 continuing review process and it says in its entirety 10 "An IRB shall conduct continuing review of research 11 covered by this policy at intervals appropriate to the 12 degree of risk, but not less than once per year, and 13 shall have the authority to observe or have a third 14 party observe the consent process and the research." 15 There is no substance, no procedures, no 16 meat, if you will. However, there have been lots of 17 requests for guidance and lots of complaints from 18 investigators, lots of beefing, because there is no 19 meat. So there really is only one regulatory 20 requirement and that's for yearly review. There is a 21 mandate to do it, but no direction on how to do it. 22 Looking at the preamble that was published 31 1 in 1981 when the regulations were promulgated, it 2 states "The precise procedure adopted by the IRB for 3 continuing review...should be left to the direction of 4 the IRB." I'll show you what has been left out in a 5 second. But the point is that the intent of the 6 regulation writers was to give wide latitude to IRBs 7 and institutions. 8 To satisfy your curiosity, if you haven't 9 already looked at the next slide, what was left out 10 was another intent embedded in the middle of the 11 sentence and that intent was without unnecessarily 12 hindering research. To restate the procedures adopted 13 by the IRB for continuing review should be left to the 14 discretion of the IRB, not Government regulators. And 15 whatever procedures are used, they should not 16 needlessly hinder research. 17 The sentence after the one I just quoted 18 states "Reporting requirements may vary from a simple 19 annual notification in the case of research involving 20 little or no risk to more frequent reporting," and 21 goes on, "or for clinical trials, the IRB may require 22 a special mechanism to carry out data and safety 32 1 monitoring functions." This is a veiled reference to 2 DSMBs and DMCs, not a requirement for IRBs to 3 accomplish data and safety monitoring. 4 So you have got to ask yourself do we have 5 and use a simple annual notification in the case of 6 research involving little or no risk? And for 7 clinical trials, can the IRB count on data monitoring 8 committees to monitor data, to carry out data and 9 safety monitoring functions or is this duty placed on 10 the IRB itself? Certainly, for the first two, it's 11 no. And for the second it's a mixed bag. 12 We have lost our way. The guidance we 13 have received and the institutional practices we have 14 developed haven't helped us out of the woods. Looking 15 at some of the guidance. The FDA says that the 16 regulations outline minimum requirements. They do not 17 provide specific instructions for IRBs on how to set 18 up their own rules for continuing review within the 19 framework of the regulations. And the FDA says the 20 regulations allow institutions or IRBs to impose 21 greater and more detailed standards of protection for 22 human subjects than those specified by the regulations 33 1 and permit each IRB to develop procedures appropriate 2 to its needs. 3 Well, so far so good. This squares with 4 the intent stated in the preamble that IRBs should set 5 their policies and procedures, but there is trouble 6 ahead. HHS has more guidance, both in terms of sheer 7 volume and direction and rules. HHS requires IRBs to 8 use all eight criteria in Section 111 for every 9 review. HHS tells us what documents are required in 10 every continuing review. HHS even gets into the 11 detail of defining the content of supposedly internal 12 institutional progress reports. 13 HHS says what we must put in IRB minutes 14 and how the deliberation and voting procedures must be 15 done and even what reports must be reviewed. As 16 indicated, I won't get into the morass of adverse 17 event reporting here, but the level of detail and 18 guidance from HHS is extremely prescriptive. HHS 19 guidance rules out grace periods under any 20 circumstances. HHS has even set a window on when the 21 IRB must do its work. Where did all that guidance 22 come from? Where does it say that in the regulations? 34 1 "Dear HHS," to paraphrase Snoopy, "I am 2 writing to you to cancel my subscription. Please, 3 remove my name from your mailing list." To be fair, 4 we in the IRB world have hounded, get it, Snoopy, 5 hounded, both the FDA and OHRP and before that OPRR to 6 give guidance. We now know that we have to be very 7 careful about what we ask for. As Dan indicated, when 8 the subcommittee first met, several questions 9 literally popped out at us. 10 When the work group had its inaugural 11 meeting, which was over the telephone, another set of 12 questions was raised. I'll walk you through our 13 preliminary thinking and again it is preliminary 14 thinking at this stage on each of these and leaning 15 toward recommendations in some places only. We would 16 really appreciate getting input later today on these 17 questions, but also on what questions we may have 18 missed or may not have addressed. 19 Question 1: When can continuing review 20 stop? The regulations do not address this issue and 21 only state that an IRB shall conduct continuing review 22 of research not less than once per year. While there 35 1 is no written guidance on when research study ends, 2 they have held that as long as an investigator is 3 controlling identifiable data, continuing review, must 4 be conducted at least annually. 5 An interesting point of discussion was 6 that HHS and FDA have different definitions for the 7 term human subject research. FDA defines human 8 subject research as the use of a test article with 9 patients or controls, i.e., clinical trials. So FDA 10 includes only living people. But HHS includes the 11 concept of private information in addition to 12 intervention with people, the non-corporeal subject, 13 if you will. 14 This impacts the second question above. 15 Must continuing review continue as long as identifying 16 data exists or is there a point where the IRB can 17 close it? An example of this situation that was used 18 in our discussions were cooperative oncology studies 19 sponsored by NIH that remain open solely to collect 20 survival data. There is no new enrollment and no 21 ongoing intervention. The only potential risk is a 22 breach of confidentiality and with the typical 36 1 safeguards in place, the risk is very low, that is a 2 low probability of the event. 3 The subcommittee basically believes that 4 the application of Section 111 to low risk research, 5 such as this, may add no value to human subject 6 protection and may not be a reasonable requirement. 7 And that, two, a revision of existing guidance could 8 help address this point, if it is stated that a study 9 ended when all interventions are over and/or when the 10 data collection is complete at the research site for 11 which the IRB has oversight. 12 Question 2: Are there circumstances where 13 continuing review can be appropriately conducted less 14 often than once per year? In the preamble, there is 15 no explanation for selection of the one year period. 16 It could have been two years or five years or six 17 months and there was discussion in there of six months 18 or a year. Many believe that for minimal risk 19 research the requirement for yearly review is neither 20 related to nor appropriate to the degree of risk. 21 However, only a change in the regulatory 22 wording would permit IRBs to set a longer review 37 1 interval. While there is no regulatory basis for the 2 current content of the continuing review process 3 itself, both HHS and FDA have pointed IRBs to the age 4 criteria in Section 111 as the measure for all 5 research, initial reviews and continuing review. It 6 makes ethical and practical sense for initial review. 7 But for continuing review, this seems to unduly limit 8 the flexibility of IRBs to employ appropriate 9 processes and procedures and criteria for ongoing 10 studies. 11 It seems to exceed the original intent of 12 the regulations for a simple process. The 13 subcommittee recognizes that any change to the 14 regulations is not to be taken lightly. We've already 15 heard from Dr. Schwetz how difficult it is to change 16 some fairly basic provisions. So the subcommittee 17 believes that wide comment from researchers, IRBs and 18 the public would be helpful regarding the applications 19 of Sections 109 and 111 to continuing review. 20 Question 3: Should categories 8 and 9 21 from the expedited review list, which was published in 22 the Federal Register in November of 1998, a revised 38 1 list, be expanded or clarified? These two provisions 2 are in your slides on Slide 43 and Slide 44. There 3 was general agreement that activities in these 4 categories, such as follow-up of cancer survivors, can 5 be of such low risk that even an expedited continuing 6 review does not meaningfully add to human subject 7 protection. The fact that there are exempt categories 8 in the regulations recognizes that not all research 9 activities require the protection provided by IRB 10 review or even informed consent. 11 Category 9 promotes flexibility in 12 continuing review based on study risk, because all 13 minimal risk studies are eligible. For minimal risk 14 activities that are not on the list published in the 15 Federal Register, however, the initial review must 16 still be conducted at a convened meeting. This is a 17 burden issue for expedited review. 18 We think that expedited review Category 19 8(b) should be interpreted so that expedited 20 continuing review is permitted if no additional risks 21 have been identified at any site in a multi-site 22 research and no subjects have been enrolled since the 39 1 prior review and none are currently enrolled at the 2 IRBs research site since the proceeding review. 3 Currently, we are told that 8(b) means no subjects 4 have been enrolled at the site ever. 5 Question 4: What is the role of the IRB 6 in literature searches of continuing review? The 7 regulations do not state or even suggest that the IRB 8 is required to perform or validate a review of the 9 literature. Reviewing the literature is a scientific 10 activity, as such, it is the responsibility of the 11 investigator. The IRB should receive the results of 12 the investigator's review, but it should not be 13 responsible for conducting it. 14 Question 5: How should exempt research be 15 handled at continuing review? One of our committee 16 members stated that this was a no-brainer. See 17 Homer's x-ray here in the corner. 45 CFR 46.101(b) 18 describes some types of human subject research 19 activities with such low risk that the regulations are 20 not applicable. Therefore, there is no requirement 21 for initial IRB review or for continuing IRB review as 22 defined in Subpart A. 40 1 OHRP cautions institutions that 2 investigators should not self-determine that their 3 research is exempt. This has created confusion and 4 most institutions now make the IRB verify exemption 5 claims. But some institutions process these through 6 full expedited procedures and even conduct yearly 7 continuing review. Steps need to be taken to clarify 8 that there is no implication that the IRB has an 9 automatic responsibility for the oversight of exempt 10 activities. The man tenet of the subcommittee is that 11 unnecessary review diminishes the quality of the 12 process overall. It hurts credibility of the IRB and 13 the regulations and it diminishes our resources. 14 Question 6: What is the role of review 15 for unanticipated problems and adverse event reports? 16 Section 103 requires written procedures for ensuing 17 prompt reporting to the IRB of any unanticipated 18 problems involving risk to subjects or others. 19 Unanticipated problem review is okay, but despite 20 having no specific regulatory basis, current HHS 21 guidance states that IRBs should even review adverse 22 events. 41 1 Because the adverse event reporting and 2 review is such a major problem and in light of the 3 fact that other groups including OHRP, NIH, FDA are 4 actively addressing this topic, further discussion and 5 the development of recommendations was deferred 6 pending progress on a solution by these other groups. 7 Question 7: What is the proper interface 8 between data monitoring committees and the IRB during 9 continuing review? Only Section 111(a)(6) addresses 10 monitoring. It states "When appropriate, there are 11 adequate provisions for monitoring the data collected 12 to ensure the safety of subjects." Because this issue 13 affects more than just continuing review, the 14 subcommittee believes that further discussion and 15 development of recommendations on data monitoring 16 committees should be a topic for the full SACHRP 17 Group. 18 That said, efforts to integrate or 19 harmonize the HHS guidance, FDA guidance and the many 20 NIH policies on data monitoring committees would 21 provide a valuable opportunity to enhance substantive 22 review, both initial and continuing. Defining an 42 1 appropriate role for data monitoring committees and 2 clarifying the interface between IRBs and DMCs would 3 reduce both investigator and IRB burden and improve 4 the safety of human subjects. 5 Question 8: What types of oversight are 6 appropriate and reasonable in continuing review and 7 what data or information improves human subject 8 protection? Both accrediting organizations have 9 standards that address continuing review. These 10 standards list the types of documents and/or 11 information that should be provided and reviewed by 12 the IRB. These lists essentially evolved from the HHS 13 and FDA Guidance Documents, but go beyond them in many 14 cases. 15 The focus of the accreditation standards 16 thus reflects the federal bias toward process rather 17 than substance. Both federal regulators and voluntary 18 accrediting organizations need to recognize and 19 support the fact that different mechanisms can be used 20 to achieve safe and ethical research. It would not be 21 useful if federal guidance was changed to provide more 22 latitude to accomplish tasks in the most efficient and 43 1 effective way for any given site only to have 2 accreditors constrict flexibility. Truly, in this 3 case, one size does not fit all. 4 Question 9: Some IRBs have established as 5 institutional policy a resubmit as new review. Is 6 this a best practices model? Resubmit as new policies 7 represent one way to enhance the process of continuing 8 review, but only one way. The subcommittee generally 9 endorsed the concept. However, as an option only for 10 those institutions that would derive a value from that 11 process. This policy in combination with a longer 12 review period might, in fact, be a truly effective 13 method for some IRBs. 14 A caution, however, the subcommittee 15 believes that placing this or any other best practice 16 in federal guidance would risk becoming a de facto 17 requirement for all IRBs. Non-regulatory and dare I 18 say non-accrediting educational outlets should be used 19 to provide information on review options and best 20 practices. So go arena or go ACRP, go NCURA, on 21 Donner, on Blitzen. 22 Question 10: Does the current HHS 44 1 guidance regarding setting the date of continuing 2 review need to be changed? The guidance states that 3 the date of the convened meeting sets the date of IRB 4 approval. Given the iterative process for approvals, 5 this guidance places an unnecessary regulatory burden 6 on the review process and does nothing to enhance 7 human subject protection. It causes artificially 8 shortened review periods and sometimes causes floating 9 expiration dates that are hard for IRBs and 10 investigators to keep track of. 11 This could be changed fairly easily by 12 allowing IRBs to set the date to the day when the 13 research receives its final approval. The 14 subcommittee believes that such a policy is fully 15 supported by the wording of the regulations, conforms 16 to the intent stated in the 1981 preamble and is 17 consistent with the regulatory authority given to the 18 IRB to extend to the chair or experienced reviewers 19 the full approval powers of the assembled board, i.e., 20 the expedited review process. 21 HHS guidance allows keeping the IRB 22 approval period constant from year to year only if 45 1 continuing review is performed within 30 days before 2 the approval period expired. The need for review to 3 be meaningful and substantive requires time for the 4 IRB to ask questions, for the investigator to 5 thoughtfully respond and for the IRB potentially to 6 seek further clarification. 7 Yet, the 30 Day Rule sets an artificially 8 short window for granting approval. You can't start 9 before the 30 days and you can't finish after the 10 expiration date. These two requirements work against 11 each other and, therefore, work against human subject 12 protection. The 30 Day Rule is practically and 13 logistically problematic for IRBs and investigators. 14 IRBs have to request reviews 90 to 120 days before the 15 expiration to ensure that they are on the shelf and 16 ready to go when the 30 day gun goes off. 17 The 30 Day Rule coupled with the 18 administrative need for advanced submission, 19 therefore, forces a review of stale information. It 20 can also generate automatic lapses if the IRB requests 21 even what would seem on the face of it to be a simple 22 clarification in the material submitted for review. 46 1 Not allow individual IRBs to set reasonable procedures 2 that are appropriate to their local setting adds 3 burden without any significant benefit. 4 The 30 Day Rule must be changed to allow 5 more flexible review schedules and more timely and 6 accurate reviews. Because the current guidance forces 7 the potential for lapses, the subcommittee looked at 8 the next question, how should temporary lapses in 9 approval be handled? Guidance states that unless the 10 IRB has reviewed and approved a research study by the 11 expiration date specified by the IRB, the research 12 must stop. 13 The IRB can find that it is in the best 14 interest of individual subjects to continue 15 participating in the research interventions or 16 interactions, but enrollment of new subjects cannot 17 occur after the expiration of IRB approval. In cases 18 where the investigator is late or delinquent in 19 submitting for review, it is reasonable to require all 20 study activities to stop. However, a lapse in 21 approval because an investigator has not submitted a 22 progress report differs from a lapse of approval when 47 1 a continuing review has been submitted and is 2 undergoing review and process by the IRB. 3 Having the IRB review separate requests to 4 allow individual subjects to continue, if it is in 5 their best interest, is unnecessary in most instances, 6 because if it's likely in the interest of one subject 7 to continue, it is likely to be in the best interest 8 of others to continue as well. OHRP agrees with this. 9 This is an example of misinterpretation of the wording 10 of guidance at some sites. Sometimes we slam our own 11 finger in the drawer, but even though we did it 12 ourselves doesn't make it hurt any less. 13 New enrollments should be stopped in lapse 14 studies for two reasons: The consent form has expired 15 and an assessment of risks and the adequacy of the new 16 consent information has not been made for new 17 subjects. So there is no problem with that procedure. 18 We all agree. It was suggested that guidance should 19 be changed so that when continuing review is under 20 way, automatic study suspension is not required when 21 the expiration date passes before review and approval 22 are complete. It should be left as an IRB option on 48 1 a case-by-case basis. Of course, IRBs should specify 2 strategies to prevent review delays and extensive time 3 in the lapse state and should specify what conditions 4 and activities will be permitted in such 5 circumstances. 6 Question 11: What does the phrase 7 verification from sources other than the investigators 8 mean for continuing review? Some IRBs have 9 established audit programs that utilize IRB staff, 10 chairs and members. Some research institutions that 11 have established human research protection programs 12 have included an audit function, usually separate from 13 the IRB, for investigator site audits as well as for 14 conducting IRB operational audits. 15 An audit function is one mechanism 16 available to institutions, but it is not an IRB 17 responsibility. Establishing audit programs is 18 appropriate, but other techniques for verification 19 exist and are useful in ensuring safe and ethical 20 research. For example, submission of the last signed 21 consent form, such as the FDA suggests. Again, the 22 subcommittee is concerned that a recommendation to 49 1 place this or any other best practice in federal 2 guidance would risk it becoming a requirement for all 3 IRBs. 4 Question 12: Does the continuing review 5 need to be performed by the same board that made the 6 initial approval? The current guidance says no and 7 the subcommittee agrees. This model has the potential 8 for lack of continuity and for continuing review to be 9 less substantive due to work load if multiple initial 10 approval IRBs are sending all continuing reviews to a 11 single continuing review IRB. But it is the 12 responsibility of institutions to ensure that 13 sufficient resources and effective procedures are in 14 place to support full compliance with the regulations 15 and to adequately protect its human subjects. 16 Question 13: What documents does the IRB 17 need to be given in order to conduct continuing 18 review? Current HHS guidance states that "All IRB 19 Members should receive and review a protocol summary 20 and a status report on the progress of the research 21 and at least one member of the IRB should receive a 22 copy of the complete protocol, including any 50 1 modifications previously approved by the IRB." 2 Confusion if not controversy exists as to 3 what constitutes a protocol summary. Guidance should 4 be clarified to state that a protocol summary may or 5 may not be a separate document. There is no need to 6 require investigators to create a new document when 7 the information is readily available in sources 8 available to the IRB. Therefore, combinations of 9 information sources, such as consent forms and the 10 continuing review application itself may constitute a 11 summary. 12 If a primary review system is used, there 13 is no added benefit of requiring that all IRB Members 14 receive an extensive summary. However, the entire 15 protocol should be available to all members on demand. 16 The regulations allow consultants to aid the IRB in 17 the review studies. The use of qualified IRB 18 professional staff to accomplish full review of the 19 protocol is a technique that some IRBs have 20 instituted. This procedure can enhance human subject 21 protections by ensuring that sufficient time and 22 attention is paid to the file and to the protocol 51 1 under review. 2 Generally, the subcommittee felt that 3 guidance should clarify that qualified IRB staff may 4 act as a consultant to the IRB and accomplish the 5 review of the full protocol in any other study file 6 documents. As more IRBs moved into the electronic 7 application, submission and review, this issue will 8 become less of a concern, because all materials will 9 be accessible to all members at all times. 10 And the last question, but definitely not 11 the least, the $64 million question, the one that I 12 think will cut across all the other subcommittee 13 deliberations is question 14: Can existing guidance 14 on, insert topic here, be consolidated and integrated? 15 There was a strong belief that the focus of regulatory 16 emphasis has become a process over substance and that 17 it does not encourage quality in review the way 18 guidance on what is expected in the substance of the 19 review would. 20 In an environment where concerns about 21 litigation and consequences of noncompliance drive 22 institutional behavior, the absence of clear and 52 1 consolidated guidance results in unrealistic demands 2 on IRBs and investigators without substantively 3 enhancing protections for subjects. For example, the 4 guidance does not provide any threshold below which a 5 change to an approved study, regardless of how 6 insignificant the change, needs to be reviewed by the 7 Board. 8 So even typographical changes get reviewed 9 in the Board. And you can see that in this slide 10 there is actually a typographical. Actually, I guess, 11 we fixed it. There is words missing at the end of 12 this last sentence. The words missing is is should be 13 it needs review. But even a change like that to an 14 approved study would require going through the Board 15 process. We feel these types of changes could be made 16 exempt from this sort of review. Incidentally, that 17 was unintentional, but well placed. 18 Guidance that is not easily accessible or 19 can only be interpreted by trained IRB professionals 20 perpetuates the misperception that IRBs are primarily 21 responsible for human subject protections. 22 Investigators and other members of the research 53 1 community need to be put back in the picture. It's 2 not all IRBs. Absence of consolidated guidance makes 3 regulatory compliance more difficult than is 4 necessary. 5 Now, IRB professionals must explore 6 extensive case law in the form of FDA and OHRP 7 determination letters, old OPRR reports, Dear 8 Colleague letters, etcetera, etcetera, for answers to 9 questions related to daily operations and decision- 10 makings. Not only is this not efficient, it's nearly 11 impossible to do. So the subcommittee feels that the 12 field needs simplified, unified and practical guidance 13 for continuing review. 14 Guidance should be readable by 15 investigators and IRB Members with examples provided, 16 standards explained and thresholds defined. Guidance 17 on the substance of review should be its focus. 18 Guidance should be permissive, not proscriptive 19 wherever possible. I thank you for your attention and 20 I'll turn it back over to Dan. 21 MR. NELSON: Thank you, Gary. I'm going 22 to turn the microphone and the laptop over immediately 54 1 to Moira Keane on behalf of the expedited review 2 working group chaired by Moira and by Tom Puglisi and 3 let them continue on with their portion of this and I 4 think we'll be in good shape to wrap up the formal 5 part of this presentation by the 10:30 break and then 6 we'll pick up after the break and have plenty of time 7 for questions and discussion. So I would encourage 8 you to make notes as you go through on any individual 9 topics or slides that you would like to return to 10 during the Q&A session. 11 MS. KEANE: Okay. Thank you, Dan, Felix. 12 I would like to also acknowledge the contributions of 13 my co-chair in this working group, Tom Puglisi. We 14 worked very fast and, I think, effectively, but we 15 recognize that there is a lot of work that we still 16 need to do in this subcommittee. One of the things 17 that strikes me as we go through the discussion today 18 is that with Subpart A, there is a great deal of 19 overlap and integration. You start to talk about 20 continuing review and you have to talk about expedited 21 review. We talk about expedited review and we're 22 talking about continuing review. 55 1 I think we are going to find that as an 2 over-arching aspect of our review of Subpart A. So 3 some of the final product and recommendations will 4 probably be an interweaving of these issues as we 5 break them out and try to deconstruct them. So with 6 your patience, we will start at that deconstruction 7 process on expedited review, but recognize that this 8 will be woven in throughout our Subpart Committee work 9 group. 10 Let me remind you of the regulatory basis 11 for the expedited review processes. We find this in 12 both OHRP and FDA guidance and regulations at 46.110 13 and at 56.110 where research that is in the categories 14 appearing on a list and also reflecting minimal risk 15 and minor changes in research that has already been 16 approved by an IRB may go through what is called in 17 the regulations an expedited review process. 18 One of the confounding aspects of working 19 in an expedited review mechanism is the somewhat 20 elusive application of a definition of minimal risk. 21 And in the regulations, minimal risk means the 22 probability and magnitude of harm or discomfort 56 1 anticipated in the research and those are not greater 2 in and of themselves than those ordinarily encountered 3 in daily life or during the performance of routine 4 physical or psychological examinations or tests. 5 One of the challenges that we will be 6 talking about a little bit later this morning is this 7 definition of minimal risk and how we work with it in 8 this modern era. When we're looking at risk, we are 9 specifically cautioned to think about the risks of 10 criminals, civil liability, financial risk, employment 11 risk, stigmatization, insurability and embarrassment 12 when we are trying to determine if a risk is truly 13 minimal. 14 We are also cautioned that the rigor of 15 review under the expedited review mechanism is 16 intended in the regulations to be just as rigorous as 17 it is at the full convened IRB, but the review itself 18 is conducted by fewer members, either the chair or 19 designee or a combination thereof. 20 Again, we may use this mechanism for 21 research that is either or both of the following: 22 Some or all of the research appearing on, again, the 57 1 list and that is found by the reviewers to involve no 2 greater than minimal risk. We are also allowed to 3 exercise this option for what is considered to be 4 minor changes in the research proposal. 5 In the next couple of slides, I have 6 paraphrased what's on the list that I keep referring 7 to, but for the actual language, you should refer to 8 the regulations and the list itself. There are nine 9 categories of research procedures that are eligible 10 for expedited review, at this time. This list was 11 revised in 1998 with input from the research 12 community, the IRB community. 13 This is a paraphrasing of the first seven 14 categories. Again, here is that overlap I alluded to 15 earlier, that two of the categories pertain to 16 continuing or continuous review of research that was 17 already approved by the IRB. Again, when we start to 18 look at some of these issues, other aspects of Subpart 19 A weave into our considerations. We are reminded that 20 informed consent under the expedited review mechanism 21 is not different in terms of its standards or its 22 application or its intended effect under an expedited 58 1 review mechanism. 2 The over-arching issue that our working 3 group was studying and working on is that expedited 4 review permits effective oversight of minimal risk 5 research while permitting the majority of IRB Members 6 to focus their efforts on protecting subject's safety, 7 rights and welfare. This is not intended to reflect 8 any shortcut in the review mechanism. To the extent 9 that expedited review can be used for minimal risk 10 research, the limited time and resources of IRBs can 11 be concentrated on protecting subjects facing greater 12 levels of risk. Again, the importance here is 13 protecting the precious resource of IRB Member time 14 and review opportunities. 15 So the next couple of slides outline the 16 questions that our subcommittee was considering. 17 Again, we are looking at aspects of conditional 18 approval. We looked at whether or not additional 19 categories may be added to the 1998 list. We are 20 considering some of the concerns and application 21 issues that we have with minimal risk. 22 We are also looking at this, again, 59 1 elusive concept of minor changes to determine how, in 2 fact, we can exercise appropriate flexibility without 3 overstepping the intent of expedited review 4 mechanisms. We were also concerned about the 5 administrative changes and I think Gary alluded to 6 this in the continuing review process as well that as 7 the IRB community and professional staff have become 8 much more professional and have developed very acute 9 review skills, there may be options for administrative 10 review mechanisms. And then the flexibility that Gary 11 was alluding to also for the local institution to 12 establish its own criteria for what constitutes 13 minimal risk is something that the subcommittee is 14 working on. 15 We are also looking at whether there is a 16 need for guidance under the expedited review 17 mechanisms for managing adverse events and 18 unanticipated problems in review. We are also 19 considering whether there is a need to clarify the use 20 of expedited review for minimal risk activities in 21 Subpart C and D Subcommittees. Again, there is this 22 overlap and this common thread that goes across the 60 1 various aspects of the Common Rule. And then, of 2 course, can the existing guidelines and 3 recommendations be consolidated? 4 So let me talk a little bit about our 5 working group process. Again, you saw that we have 6 met a couple of times via telephone. We have met in 7 person a couple of times. There also were numerous 8 exchanges via separate conversations as well as emails 9 across the group membership. Some of us also 10 volunteered or had delegated the responsibility to 11 confer with other colleagues, so this was not an 12 exclusive activity to the working group of the 13 subcommittee. 14 We did consult with various professional 15 associations and colleagues who have expressed 16 concerns about expedited review. We also attempted to 17 solicit comments from the general IRB administrative 18 community, an IRB professional community, concerning 19 their expectations about expedited review. These 20 again are very preliminary findings, almost anecdotal, 21 at this point, but we want to make you aware of some 22 of the sort of feelings across the field when we try 61 1 to approach the expedited review concept. 2 In fact, what we found was that there was 3 a general lack of enthusiasm for changing the list. 4 In fact, many of us heard the phrase "be careful what 5 you ask for" when approaching this set list as it 6 exists right now. There appeared to be some 7 reluctance to change what some institutions, some 8 leaders believed, in fact, was some flexibility that 9 we already had given the current list. 10 There was also a perception that IRBs and 11 IRB professionals were reluctant to exercise the 12 flexibility that some perceive within the list and 13 within the definitions of minimal risk and minor 14 changes. That, in fact, a very conservative approach 15 was being taken by many institutions when it came to 16 exercising the flexibility under expedited review. We 17 believe that that was as a result of a fear that using 18 expedited review suggests something of a shortcut in 19 the regulatory compliance aspect of our review 20 processes. 21 And that, in fact, expedited review 22 process may be perceived either by researchers or by 62 1 subjects as trivializing the research itself, not an 2 assessment of the relative risk and potential harm 3 from the research proposal. IRBs quite commonly 4 expressed a fear of regulatory sanction if the 5 decision to expedite a project was ever questioned. 6 Now, again, there isn't a lot of data to suggest that 7 this happens, but the perception that there could be 8 sanction exists out there. 9 The other aspect that we certainly were 10 aware of and had validated through this consultation 11 process was that IRB Members generally tend to be risk 12 averse. That if we can imagine something happening, 13 we believe that, in fact, it will happen. And that 14 flies in the face of our making an assessment about 15 the probability or magnitude of harm, but it is 16 something that IRBs tend to develop a worst case 17 scenario approach to assessing potential risk. 18 And we have found very, very compelling 19 issues associated with reviewing social, behavioral 20 and educational research through an expedited review 21 mechanism and I think there is more work to be done in 22 this area as we consulted with professional 63 1 associations and colleagues who struggle with this on 2 a daily basis. 3 So we want to talk a bit about our 4 questions and the charge that we had for expedited 5 review mechanisms. The issue of concern was the lack 6 of consistency between OHRP and FDA recommendations on 7 expedited review. There are multiple documents that 8 talk about expedited review and brand new researcher, 9 brand new professional administrator looking into how 10 to manage expedited review is likely to be confounded 11 by the many, many sources of authority on how to 12 manage expedited review. 13 Our recommendation, and again these are 14 very preliminary, is that OHRP and FDA should issue 15 joint consolidated guidance on expedited review. The 16 archived or obsolete guidance that we find when we do 17 searches on the HHS website should be retired and 18 removed from the searchable sections of the website or 19 should be labeled as obsolete. 20 We discussed at some length, and this is 21 an area that I think is still requiring some 22 discussion, but the subcommittee is quite concerned 64 1 about the convened review stipulations for approval 2 concept, which is that many convened IRBs use a 3 stipulation or conditional approval mechanism to 4 define and permit timely verification by the IRB 5 Chairperson or designed Member of clarifications or 6 modifications needed or required for research to go 7 forward. 8 So following the convened meeting, there 9 is correspondence that goes to the researcher 10 outlining the kinds of changes that are required 11 before you get a green light to go ahead with the 12 project. The current guidance limits the use of this 13 stipulation mechanism to situations requiring simple 14 concurrence by the investigator to very specific 15 language that has been dictated by the IRB. We 16 believe that this limitation on the stipulation 17 mechanism is needlessly restrictive and incompatible 18 with the latitude permitted to chairpersons in their 19 review of other "minor" changes in review. 20 A possible recommendation is that IRBs 21 should be permitted to describe in their written 22 policies and procedures the stipulation mechanism that 65 1 they will use for defining minor changes required for 2 approval of proposed research under which the IRB 3 Chairperson or the designed IRB Member reviewer may 4 exercise reasonable judgment in verifying that the 5 stipulations of the convened IRB have been satisfied 6 and/or a qualified IRB Administrator may verify that 7 the investigator has implemented specific language, 8 either in the protocol, the consent documents or 9 advertisements, the language that was dictated by the 10 convened IRB and requiring no subjective judgment on 11 the part of the reviewer. And again, we believe that 12 this process is in keeping with the original intent of 13 the regulations and that over time the evolution of 14 guidance has become more restrictive in this aspect. 15 With respect to administrative changes to 16 approved research, again, IRBs are often on the 17 receiving end of changes to approved research that are 18 entirely administrative or clerical in nature. It is 19 counter-intuitive to ask a convened IRB to approach 20 these very minor changes when they have a full slate 21 of potentially risky research to review. Again, this 22 is an area not for shortcuts in our work burden or in 66 1 our work load, but an actual appreciation for reducing 2 the regulatory burden. 3 Our recommendation here is that IRBs 4 should be permitted to define in their written 5 policies and procedures changes to approved research 6 that can be implemented by qualified IRB staff. That 7 is to say that we wouldn't even involve the IRB Chair 8 or designed expedited reviewer at this point. Such 9 changes could, in the policies and procedures, be 10 limited to those that are entirely administrative or 11 clerical in nature and have no effect on the conduct 12 of the research, the underlying science or on the 13 potential willingness of subjects to continue their 14 participation in a research project. Again, we 15 believe that this is in keeping with the original 16 intent of the regulations and recommendations that 17 were set forth in 1981. 18 The review of activities not involving 19 human subject research is an aspect that falls 20 somewhat under the expedited review, but again sort of 21 interweaves across all of the Subpart A portions of 22 the regulations. Again, there is a lack of 67 1 understanding about the regulatory definitions of 2 research and human subject. And Gary alluded to this 3 earlier when he was looking at the definitions under 4 the rubric of continuing review. 5 What happens then is that IRBs find 6 themselves reviewing activities that do not constitute 7 human subject research. Reviewing these activities 8 really deprives the IRB Members of valuable and 9 limited time that we could use more productively and 10 apply more effectively to the review and oversight of 11 research that involves potential for serious risks. 12 It, in fact, generates considerable resistance, if not 13 hostility, from those performing the activity, meaning 14 the researchers whom we are trying to help as they 15 protect the research subjects, and, frankly, it 16 undermines the respect for the IRB process and it 17 minimizes it suggesting that it is merely a 18 bureaucratic hurdle. 19 Our recommendation here is that the 20 definitions of research and human subject should be 21 clarified in the following ways: Here is the 102 22 definition. Again, that's in your regulations. 68 1 "Systematic investigation designed to develop or 2 contribute to generalizable knowledge." In our 3 thinking currently, the systematic definition should 4 be broken out to suggest that it means it is carried 5 out according to a plan that allows conclusions to be 6 drawn. 7 Designed means that it is intended or with 8 the purpose of establishing either by the 9 investigator's expressed intent or the investigator's 10 use of the information or conclusions resulting from 11 the investigation. So again, we are looking at a bit 12 more detail to flesh out what we are talking about 13 when we say design. And in terms of generalizable 14 knowledge, meaning that the information represented as 15 applicable to persons and institutions beyond the 16 institution or the location of the research, in which 17 the information was obtained. 18 I'll talk a little bit more about why 19 these become very confounding. In the human subject 20 definition, in the regulations, we are talking about 21 a living individual about whom an investigator 22 conducting research obtains data through intervention 69 1 or interaction, that's fairly straightforward, or 2 through identifiable private information. You can 3 read the definition there. 4 The concern here is that the identity of 5 the subject is or may readily be ascertained by the 6 investigator where they can identify through 7 information that's publicly available or easily 8 obtained. Information may be deemed non-identifiable 9 where investigators provide a signed attestation that 10 they will neither attempt to identify subjects nor 11 knowingly obtain or accept information through which 12 they may identify subjects. 13 This is a very compelling need on the part 14 of many researchers in the social sciences who are 15 working with very large data sets. And there is, I 16 think, additional input that we can get from some of 17 those researchers on how to best handle this type of 18 research without creating unnecessary burdens or 19 obstacles. The identity of the subject is or may 20 readily be associated with the information, means the 21 investigator can identify subjects through a code or 22 other linking information to which the investigator 70 1 has access. 2 Again, with good professional guidance and 3 guidelines on how this research should be conducted, 4 the information could be deemed non-identifiable where 5 investigators again provide a signed attestation 6 countersigned by an individual or entity holding the 7 key to the identifying codes. But the investigators 8 will neither be given nor will they accept the key 9 through which they may identify subjects. 10 Again, this is very compelling when you 11 talk to scientists who are dealing with mass data sets 12 who are trying to address very compelling scientific 13 questions, but are hindered by the current regulatory 14 interpretations. 15 There are also lots of activities that do 16 not involve human subject research, as I alluded to 17 before, that are not encompassed within the above 18 definitions of research and human subject, do not 19 require IRB review. However, there are some gray 20 areas here that again become very confounding for IRB 21 Administrators, for IRB Chairs and for the research 22 community and we want to go through some of those and 71 1 point out some of the concerns that we have, both 2 generally under Subpart A, but also under expedited 3 review. 4 For example, journalism interviews are 5 investigations, typically, do not meet the definition 6 of research or research with human subjects. However, 7 there are exceptions, such as a journalist conducting 8 a series of interviews conducted not for news 9 purposes, but to develop a theory of personality and 10 social development. This would, in fact, meet the 11 definition for research and human subject research. 12 Oral history interviews, and we have heard 13 a lot about this in recent years, an example of an 14 exception requiring IRB review is that a historian 15 conducts a series of interviews to develop or confirm 16 a generalized economic or political hypothesis or 17 theory. Again, we have crossed from the not research 18 subject to IRB review or jurisdiction into research 19 that is. 20 Another area of interviews or observations 21 conducted by an architect for use in designing a 22 structure, at first blush, suggests that this is not 72 1 something that would come under IRB scrutiny, but an 2 exception might actually include interviews conducted 3 to develop or confirm a hypothesis through a theory of 4 architectural design. Again, you're getting 5 information from individuals about individuals and 6 their perceptions. 7 Another area that has a great deal of work 8 ahead of us in terms of proper application is student 9 research activities. Very often students are learning 10 to become researchers. This is the next generation 11 that we are trying to bring along as ethical, 12 responsible researchers, but often they are, in fact, 13 conducting research with an intent to develop or 14 contribute to generalizable knowledge. And when they 15 are doing that, they do fall under IRB jurisdiction or 16 review. 17 Quality assurance, program evaluation or 18 "institutional research activities" are often 19 considered to be outside of IRB jurisdiction, again at 20 first blush. But an exception that might require IRB 21 review is that program evaluation that's conducted to 22 identify techniques that can be applied to another 73 1 organization's programs or services crosses the line 2 to that generalizable knowledge aspect of the 3 definition. 4 And also, again with feasibility studies, 5 to determine the potential utility or viability of a 6 specific proposed service or facility often would 7 suggest that it's outside of IRB jurisdiction, but an 8 exception again would be that feasibility study that 9 is intended to be generalized to multiple services or 10 facilities and, again, we're seeing more and more of 11 that kind of creep in the interpretation and 12 application of some of these methods. 13 One of the issues that we have been 14 grappling with, and I alluded to earlier in the 15 presentation, was that the expansion of the categories 16 might be under consideration for our final 17 recommendations. Our concern is that current 18 expedited review categories may unnecessarily restrict 19 the use of expedited review procedures. 20 There are two possible recommendations 21 under consideration and we would suggest that these 22 are very preliminary, at this time, but the 74 1 possibility of expanding the expedited review 2 categories specific to Category No. 7 on the list, 3 which is research on individual or group 4 characteristics, which is in many instances perceived 5 as kind of a catchall category for much of the 6 research that happens in social, behavioral and 7 educational arenas, human factors evaluation, quality 8 assurance methods and so on. 9 Divide that into two categories and 10 provide additional examples, such as we have suggested 11 above. The division of this category might assist 12 IRBs in their review of this very challenged research 13 area at this time and, again, in accordance with 14 written policies and procedures at the local IRB level 15 permit IRBs to utilize expedited review procedures for 16 all minimal risk research, not just to a specific 17 list. 18 There are some other issues that are on 19 the table, but again we need to spend more time to 20 flesh those out, the question of whether there's a 21 need for additional guidance concerning the 22 interpretation of minimal risk, and Dan is going to 75 1 talk about that a little bit more this morning, 2 because this is an area that needs considerable 3 dialogue within the subcommittee and also across 4 research communities. 5 Is there a need for clarification that 6 expedited review is generally appropriate for review 7 of recruitment materials, advertisements, etcetera? 8 Again, this is an area where IRBs have been reluctant 9 to exercise the flexibility that is already available 10 to us under FDA guidance. We believe that that should 11 be emphasized and that it is sufficient. 12 Can an expedited reviewer disapprove or 13 require revisions and minor proposed changes to the 14 ongoing research without referring the matter to the 15 convened IRB? In this instance, where an expedited 16 review mechanism is employed, the reviewer, through 17 professional judgment and a well-articulated review 18 based on the regulations and requirements, determines 19 that there are some aspects of the project that do 20 need minor revision. In some very conservative 21 interpretations, it would suggest that those revisions 22 would need to go back to the convened IRB, not handled 76 1 through the expedited review mechanism. 2 We believe that, again, with some 3 reemphasis of the existing opportunities under 4 expedited review, most IRBs are able to currently 5 handle this situation through negotiation between the 6 investigator and the IRB reviewer. But again, there 7 should be explicit permission for that under the 8 guidance materials. 9 The other question about is there a need 10 to clarify the use of expedited review for minimal 11 risk activities and research involving children or 12 prisoners or will this be addressed by Subpart C and 13 D? Again, this is that overlap we have been talking 14 about. We believe that those subcommittees are 15 working on these aspects and will provide us with 16 additional guidance. 17 And is there a need for guidance on the 18 appropriate use of expedited review of adverse events, 19 serious adverse events and unanticipated problems? 20 Yes, we also agree that there is need for more 21 guidance, but we also suggest that this will be 22 handled outside of the Subpart A Subcommittee work. 77 1 So as I have said repeatedly, this is a 2 work in progress. The expedited review mechanism is 3 a mainstay of IRB operations and human subjects 4 protection. It is one of the mechanisms by which we 5 can facilitate good, ethical research through a 6 mechanism of IRB review that both satisfies the 7 regulatory requirements, provides service to 8 researchers and, the ultimate, protects research 9 subjects. 10 We have additional work ahead of us, so 11 that we can, as we were coining a phrase on our 12 subcommittee, allow expedited review to be all that it 13 can be. So with that, I'll turn it over to Dan. 14 MR. NELSON: Well, thank you to both Moira 15 and Gary for walking us through. Not only do they 16 have the ability to take us through 120 slides in an 17 hour and 15 minutes or so, but they have the 18 knowledge, most importantly, that supports all the 19 work that went into this and we owe them a debt of 20 thanks. And Felix and I are both relieved that we're 21 not sitting here trying to walk you through all the 22 work that the working groups have done and continue to 78 1 do. 2 Ernie, I will let you pound the gavel, but 3 I think we would be ready for a break as scheduled, at 4 this point, and then reconvene to wrap up the last few 5 slides and then open it up for discussion and comment. 6 CHAIRMAN PRENTICE: Yes. The break is 7 actually scheduled for 10:30. It's 10:15 by my clock. 8 It depends upon whether or not you want to take a 9 break now and then come back and do minimal risk or 10 would you like to do minimal risk? Your call. 11 MR. NELSON: Let's let everybody have a 12 break right now and then we'll be in good shape. 13 CHAIRMAN PRENTICE: Okay. We'll reconvene 14 at 10:35. 15 (Whereupon, at 10:17 a.m. a recess until 16 10:36 a.m.) 17 CHAIRMAN PRENTICE: Okay. Dan, would you 18 take over, please? 19 MR. NELSON: Thank you, Ernie. So we have 20 just a few slides that are in your handouts to finish 21 up the formal part of this presentation, as it were, 22 and then would welcome thoughts and reactions and 79 1 comments. The last part of this is what we spent most 2 of the day at our last on-site meeting as a 3 subcommittee discussing, and those are considerations 4 on minimal risk, the definition of minimal risk, 5 interpretations, applications, the impact on this 6 important process. 7 You might ask why minimal risk, why did 8 this filter to the top, why are we singling this out 9 as opposed to other aspects? And I will admit that as 10 we looked at the long laundry list that I showed you 11 of possible topics, we came to a working hypothesis at 12 least that we would avoid, we wouldn't wade into 13 definitions, that that was probably better left off 14 the table from our deliberations. 15 We are not, I think, big headed enough or 16 maybe pig headed enough to think that we are going to 17 redo and improve on the work of the original 18 commission that wrote the Belmont Report, the original 19 framers of the regulations. There was a lot of 20 careful thought and consideration that went into every 21 word of the definitions and of the regulations, and we 22 don't see that as our job to redo that. 80 1 On the other hand, we came to the 2 inescapable conclusion that things have changed, that, 3 in fact, dealing with definitions and dealing 4 immediately with the definition of minimal risk was 5 impossible to avoid. We recognized that, as with so 6 many other aspects of what we're talking about, things 7 have changed in the last 20 or 30 years, that 8 interpretations, applications have evolved and changed 9 and solidified, that problems have become apparent 10 over time. 11 And that led us, again, to the inescapable 12 conclusion that we had to focus on minimal risk and, 13 in fact, we couldn't even get through the first two 14 topics that you heard about from Gary and Moira, 15 continuing review and expedited review, without 16 bumping headlong into the definition, the application, 17 the interpretation of minimal risk, because it's 18 interwoven through everything, so much of what we do. 19 So with that, a few comments, and these 20 are even more provisional, more preliminary thinking 21 than what you just heard. The subcommittee is really 22 just having a chance to bring together information to 81 1 reach out to people, to get educated on this topic and 2 then to start to think about the finer points that 3 might need tweaking or reinterpretation. 4 I want to acknowledge Chairman Prentice 5 for his donation of some slides that we'll use on the 6 next few just to provide background on minimal risk, 7 and the first is here. Ernie has nicely captured, and 8 I didn't change a single word in describing what Ernie 9 called the risk escalation principle of protection by 10 which he means and we understand that as the risk of 11 research rises above the threshold of minimal risk, 12 however we define that, there are restrictions and 13 additional protections, particularly for vulnerable 14 subjects that come into play. 15 That's reflected in a slide that I had 16 developed quite independent from Ernie and as I try to 17 explain to audiences, investigators and IRB Members 18 how the definition of risk and minimal risk is 19 operationalized as we apply the regulatory categories, 20 the options for review, as one increases risk or the 21 potential risk of harm or discomfort in proposed 22 research, we then, as you well know, can apply 82 1 different levels of review ranging from exempt review 2 to expedited and then minimal risk provides that 3 threshold. The orange line there, that would kick a 4 review over into the full convened meeting category. 5 That's just one example of where minimal 6 risk does impact this process in a daily, ongoing and 7 meaningful way. There are many other references woven 8 throughout 45 CFR 46 to minimal risk and those are 9 itemized on this slide. The first of those is the one 10 I just described, making determinations as to what 11 research could be eligible for expedited review, as 12 opposed to the remainder that requires full board or 13 convened meeting review. 14 There are other citations or references, 15 however, including the handling of explanation of any 16 available compensation for subjects, the explanation 17 of any available treatments. These are required to be 18 considered and addressed and explained to subjects 19 where studies involve more than minimal risk, and that 20 is not to say that studies that involve no more than 21 minimal risk often do address those same issues, both 22 those are in the regulations as requirements. 83 1 Minimal risk factors into the 2 determination of waivers or alteration of consent 3 process or content under 46.116, and waiver of signed 4 consent forms or written documentation of consent. 5 The definition of minimal risk also comes into play in 6 the Subparts B, C and D for research involving 7 pregnant women or fetuses, prisoners or children and 8 the Subpart D Subcommittee that you will hear from 9 later today has spent a great deal of time, because 10 there we actually get multiple references to not 11 greater than minimal risk, greater than minimal risk, 12 more than minimal risk and a minor increase over 13 minimal risk. And if it's difficult enough to 14 understand and apply minimal risk, then try to 15 understand and apply a minor increase over minimal 16 risk, which lends it even more shades of gray. 17 So these are the annual and you will also 18 note some inconsistencies, although we're not 19 convinced necessarily this is a big source of problem 20 or error, but there are some inconsistencies in even 21 the words used to refer to this benchmark, this 22 threshold woven throughout the regulations. 84 1 This is the definition of minimal risk in 2 46.102 in Subpart A. Moira has already reviewed it, 3 but because it's so central to this topic, I will just 4 review again briefly. Minimal risk is defined as the 5 probability and magnitude of harm or discomfort 6 anticipated in the research are not greater in and of 7 themselves than those ordinarily encountered in, and 8 I have highlighted the operational terms that become 9 a focus of much discussion, those encountered in daily 10 life or during the performance of routine physical or 11 psychological examinations or tests. 12 Ernie in his background prep for us on 13 this topic pointed out that in the preamble in 1981 to 14 the regulations, there were some clarifications from 15 both HHS and FDA on the definition of minimal risk, 16 and HHS wrote that or the preamble clarified that HHS 17 in the proposed regulations used the terminology 18 "healthy individuals." 19 In light of the public comments on this, 20 however, HHS has reworded the final regulation to 21 reflect its intention that the risks of harm 22 ordinarily encountered in daily life means those risks 85 1 encountered in the daily lives of the subjects of the 2 research, a historical clarification that we'll return 3 to in our discussion. 4 The FDA in that same preamble noted that 5 this definition takes into account the fact that the 6 risks in the daily life of a patient are not the same 7 as those of a healthy individual and uses the risks in 8 daily life as the standards for minimal risk. Now, 9 you will note it doesn't say whose daily life and we 10 could debate that and we won't hold Dave LePay 11 responsible for clarifying 24 year-old writings, but 12 even this clarification begs further clarification, I 13 think it could be argued, but we're left today 14 applying in the modern environment in variable ways. 15 The definition of minimal risk in Subpart 16 C which, as you know, deals with the research 17 involving prisoners is as follows: Minimal risk is 18 the probability and magnitude of physical or 19 psychological harm that is normally encountered in the 20 daily lives or in the routine medical/dental, we 21 tossed in for good measure which was not in the parent 22 definition, or psychological examination of healthy 86 1 persons. So there we have the healthy persons 2 standard embedded in wording, as opposed to a preamble 3 clarification. 4 The National Commission in its original 5 report and recommendations on research involving 6 children wrote that minimal risk is the probability 7 and magnitude of physical or psychologic harm that is 8 normally encountered in the daily lives or in the 9 routine medical or psychological examination of 10 healthy children. 11 There is no definition of minimal risk, at 12 least that made it into the regulations, in Subparts 13 B and D, and Ernie has clarified in this slide we 14 borrowed from him that the failure to include a 15 definition of minimal risk in those subparts means 16 that we basically fall back to the definition in 17 Subpart A, which then applies to research involving 18 pregnant women, fetuses, neonates and children. 19 The absence of a definition in Subpart D 20 led your group with the subcommittee that has been 21 focusing on this and, again, you will hear more from 22 them this afternoon, and I should add a special thanks 87 1 to the co-chairs of that group for flipping in the 2 agenda, so that I could go back on vacation. 3 And I'm sorry to miss this afternoon, but 4 I know you have been working very hard and this is the 5 latest iteration that SACHRP endorsed, I believe, on 6 April 18, 2005, clarifies that the definition of 7 minimal risk at 45 CFR 46.102, when applied to Subpart 8 D, should be interpreted as those risks encountered by 9 normal, average, healthy children living in safe 10 environments in daily life or during the performance 11 of routine physical or psychological exams or tests. 12 OHRP has never issued official guidance 13 regarding the definition of minimal risk. However, 14 when asked, OHRP recommends use of the healthy person 15 standard when applying the provisions of Subpart A, 16 and this has been confirmed with Mike Carome on 17 repeated occasions and this has been the working 18 guidance, if you will, from OHRP. 19 So on this background and with a lot of -- 20 we actually held several teleconferences and then in- 21 person meetings to really burrow into all corners of 22 this two word phrase that has such an impact on the 88 1 day-to-day application of the regulations and in an 2 IRB practice, and there were several issues that 3 filtered to the top that we have itemized here on 4 these next two slides or three slides. And this is by 5 no means all of them, but it's the constellation of 6 concepts and issues that we have been grappling with. 7 And I will just say right now we haven't 8 reached consensus on which of these really needs 9 grappling with most and which, although perhaps an 10 annoyance, might just be left as is and we would 11 invite your thoughts to help us focus our thinking 12 further on this. 13 Whose daily life are we talking about? 14 You have seen reference to the healthy person standard 15 and the alternative interpretation would be or 16 application would be to the subjects of research 17 recognizing that the subjects of an individual 18 research study may or may not be healthy, may be in 19 different circumstances than the "healthy general 20 population." 21 Does the relative standard, that is 22 parsing it out a bit so that you might have a 89 1 different threshold, if you will, for a given study, 2 depending on who the subjects are of that study, does 3 that create a slippery slope, and many of us would 4 argue that yes, it does. If, for example, you have a 5 person with a disease or an illness who is undergoing 6 invasive treatments, does adding one more invasive 7 treatment or procedure to somebody already getting 8 those in the course of their clinical care, does that 9 still constitute minimal risk, because they are 10 already exposed to a certain level? Does that create 11 an unacceptable, untenable, ethical slippery slope? 12 Is the healthier general population 13 standard also relative if that safe environment we're 14 talking about -- is that really the same from, for 15 instance, my area of Chapel Hill versus downtown 16 Detroit versus Baghdad? Where are your subjects 17 located and what general population are we talking 18 about if we chose to define it in that way? 19 Are we talking about a healthy individual 20 who is a skydiver or a healthy couch potato or a 21 healthy SACHRP Member, which of course may be all over 22 the map in terms of the kinds of activities that we 90 1 engage in daily life. 2 Do clarifications in the 1981 preamble set 3 a precedent? Do we need to adhere to what was already 4 relatively clearly laid out back in 1981 as the 5 subjects of research for creating a sort of -- well, 6 creating a relative standard? Does the 2005 April 7 SACHRP recommendation on Subpart D set precedent? 8 Since you have already deliberated carefully on this 9 and adopted that, are we beholden to apply that to the 10 Subpart A regs? 11 Another way to ask the same question, are 12 we bound to have the same interpretation in research 13 that involves adults, as opposed to research that 14 involves children, or does it make sense and is it 15 permissible to have a different interpretation and 16 application? And I can tell you we have members just 17 of our subcommittee who would argue in either 18 direction on that, and one reason we haven't come to 19 consensus and why we want to proceed carefully with 20 your input. 21 Does the current definition imply 22 equivalence, and I would refer you back to the slide 91 1 where the current definition is, which is on Slide 125 2 in your handouts, and there is an "or" in there, the 3 risks encountered in daily life or during the 4 performance of routine physical or psychological exams 5 or tests. Does that imply an equivalence between 6 daily lives or that examination or testing or is one 7 greater than the other and, therefore, should we 8 default to the lower risk of those? And we can talk 9 more about what we mean by that, if that's not clear, 10 as we enter the discussion period. 11 Is it possible to downgrade greater than 12 minimal risk to minimal risk research via minimization 13 procedures? We're charged under 111 to ensure that 14 risks are minimized to the extent possible. It 15 doesn't mean they are eliminated all together, but I 16 have heard IRBs approach this and apply this as if 17 they were able to take research that we would all 18 agree is inherently greater than minimal risk 19 research, but because they have done a good job of 20 imposing procedures, working with the investigator to 21 control the risk, does that knock it down, if you 22 will, to no greater than minimal risk or does that 92 1 intrinsic risk remain a constant and we just hope that 2 we have done a good job to minimize the exposure to 3 risk? 4 Do we need to harmonize differences across 5 the regulations? We have pointed out there are some 6 differences in wording and references and how those 7 are understood and applied. Is that a real problem 8 that needs to be addressed? 9 We have spent a lot of time talking about 10 the differences between biomedical and social and 11 behavioral research. There is, I think it can be 12 argued, an overestimation of risk particularly in 13 social and behavioral research. Do we need to 14 acknowledge this and address this at a regulatory 15 level or in a guidance on regulations level? 16 Would a list of examples be helpful? 17 Again, the Subpart D group has already come up, I 18 think, drawing on the NHRPAC table that spelled out or 19 that gave examples of minimal risk versus minor 20 increase over minimal risk versus greater than minimal 21 risk procedures, not intended to be all inclusive, but 22 at least a helpful place for investigators and IRBs to 93 1 find themselves in there and extrapolate to their own 2 research proposals in a way with at least more 3 certainty and more guidance than simply having the