1 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTIONS MEETING THURSDAY NOVEMBER 2, 2006 The Advisory Committee met in the Galaxy Room in the Sheraton National Hotel, 900 South Orme Street, Arlington, Virginia, at 8:30 a.m., Ernest Prentice, Ph.D., Chairman, presiding. PRESENT: ERNEST D. PRENTICE, PhD Chair BERNARD A. SCHWETZ,DVM,PhD Executive Secretary CATHERINE SLATINSHEK, MA Executive Director JEFFREY BOTKIN, MD, MPH Member CELIA B. FISHER, PhD Member MYRON GENEL, MD Member NANCY L. JONES, PhD Member DANIEL K. NELSON, MS, CIP Member NEIL R. POWE, MD, MPH, MBA Member JAMES H. POWELL, MD Member FRANCINE C. ROMERO, PhD, MPH Member SAMUEL TILDEN, MD, JD, LLM Member Ex Officio Members KATHRYN LYNN CATES, MD U.S. Department of Veterans Affairs ROGER CORTESI Environmental Protection Agency SALLY FLANZER Agency for Healthcare Research and Quality DENISE GEOLOT, PhD, RN HRSA PETER T. KIRCHNER, MD Department of Energy WARREN E. LUX, M.D. Environmental Protection Agency 2 Ex Officio Members (continued) JEFFREY W. RODAMAR Department of Education SANDRA SCHNEIDER, PhD National Science Foundation ALSO PRESENT KELLEY BOOHER Office of Human Research Protections MICHAEL CAROME Office of Human Research Protections JULIA GOREY 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 I N D E X PAGE Remarks and farewell to departing 4 SACHRP members John Agwunobi, M.D. Assistant Secretary for Health Welcome: Opening Remarks 15 Ernest Prentice, Ph.D. Chairman, SACHRP Report of Issues 24 Bernard Schwetz, DVM,PhD. Director, OHRP Report of Subpart A Subcommittee 44 Felix Gyi, MBA, Pharm.D. Dan Nelson, MS, CIP LUNCH Report of Subpart A Subcommittee 170 Public Comment 257 Discussion and Wrap-up 271 4 1 P R O C E E D I N G S 2 Time: 8:34 a.m. 3 CHAIRMAN PRENTICE: Good morning, 4 everybody. Welcome to our November 2-November 5 3 meeting of SACHRP, Secretary's Advisory 6 Committee on Human Research Protection. 7 We are going to alter the agenda 8 slightly, if we may, and what I would like to 9 do is recognize Dr. John Agwunobi, who is the 10 Assistant Secretary of Health and Human 11 Services. He was going to make some remarks 12 after we went through the beginning of the 13 agenda, but we have rearranged the agenda in 14 accordance with his schedule change. 15 So, Dr. Agwunobi, would you like 16 to talk from there or would you like to come 17 up here? 18 ADMIRAL AGWUNOBI: Whatever your 19 pleasure is, Mr. Chairman. 20 CHAIRMAN PRENTICE: Why don't you 21 come up here? 22 ADMIRAL AGWUNOBI: All right. I 5 1 have been given some speaking points by Cathy 2 and others, and I have left them there, 3 because I would rather speak from the heart. 4 Cathy, forgive me. I know how much work you 5 put into those notes. 6 My name is John Agwunobi. A 7 number of you know me, having listened to my 8 ramblings on more than one occasion. I know 9 there are a number of new members of the 10 SACHRP family here today. 11 I have been advised that today is 12 an entirely sad day for SACHRP. This 13 organization, this wonderful group that has 14 done so much to further human research 15 protection, has been led for a number of years 16 now by a chairman who I have come to know 17 fairly well. 18 Ernie -- Dr. Prentice -- has 19 offered SACHRP the kind of leadership that has 20 allowed it to go places that its predecessor 21 couldn't go, has allowed it to take on issues 22 that its predecessor committee was unable to 6 1 take on. He has built his leadership of 2 SACHRP on the power of relationships, his 3 relationships with each and every one of you, 4 his relationship with me, his relationship 5 with Bern and OHRP. 6 That skill, that ability to 7 develop and nurture trusting relationships has 8 allowed him to leverage much more than just 9 your expertise, much more than just your 10 charter, as he has led this organization to, 11 I think, great places. 12 Bern pleaded with me to not let 13 Ernie go. I'll be candid. He pleaded in 14 writing and verbally, face to face and over 15 the phone. At one point, I sensed that he was 16 deeply disappointed in me and angry at me. He 17 still today, this morning, was advocating 18 strongly. 19 I have explained that this 20 administration -- we try to rotate through 21 chairmanships, through significant appointed 22 positions, as much as we can. It is a 7 1 philosophy more than anything else. But I 2 must concur. I must concur that not having 3 Dr. Prentice serve as Chair going forward is 4 going to be a significant challenge for us all 5 to overcome. 6 I would urge all of you, before I 7 go any further, to join me in thanking Dr. 8 Prentice for his service. 9 (Applause.) 10 Now I have pleaded with him just a 11 little this morning as I urged him to consider 12 serving on one of our subcommittees going 13 forward, that his expertise and his unique 14 approach to these issues is still needed. 15 Whether or not he takes me up on that offer or 16 not is yet to be said. 17 I understand that SACHRP has taken 18 on a number of key issues in recent meetings: 19 Human research protection as it relates to the 20 incarcerated individual; human research 21 protection today as it relates to individuals 22 who are decisionally impaired. 8 1 I look at those two subjects and 2 realize that is the reason -- those 3 populations are the primary reason we need to 4 have advice from individuals who are expert in 5 this field, people who can come together and 6 help us not only protect everyone, assure that 7 everyone is protected, but allow us to 8 understand the very unique needs of special 9 populations. 10 So I applaud your work, and await 11 with great anticipation the results of your 12 deliberation. I know for a fact, because Bern 13 and I are scheduling that he is going to come 14 in and visit with me on the work that you did 15 in your prior meeting, the last meeting, on 16 the work that IOM and subsequently SACHRP have 17 done specifically as it relates to individuals 18 who are incarcerated as it relates to 19 research. So I look forward to that meeting 20 where you come and brief me. 21 I intend -- and I say this only 22 because today is a transition meeting between 9 1 old leadership and new. I intend to stay 2 actively and personally involved in your work. 3 I have a very personal affinity to it. It is 4 something I take to be very important, and I 5 want to be personally involved. 6 I recognize as well that I have a 7 distinct obligation to translate your work 8 into Department level policy. That is my 9 role, and so I am going to be around even 10 after Ernie leaves. I will be around. You 11 will be seeing me at every meeting or every 12 one I can get to. If I am in the country and 13 I am not otherwise engaged, I will be here. 14 I recognize that today I have some 15 formal responsibility on the agenda. Cathy, 16 if you would help walk me through those 17 responsibilities, I will dispense with them 18 quickly so that you guys can get to work. 19 As is my custom, I would urge the 20 Chairman after I am done if he would allow me 21 to engage in conversation with members of 22 SACHRP. They may have questions or comments 10 1 for me. Mr. Chairman? I'll take his silence 2 to mean yes. 3 I have received my orders. There 4 is a very special order that they would like 5 me to proceed with. I recognize I have spent 6 an inordinate amount of my speaking time here 7 this morning speaking to the Chairman and to 8 his leadership, but there are others that have 9 worked extremely hard on SACHRP and are also 10 rotating off of the committee that I would 11 love to recognize. 12 They are, of course, Dr. Nancy 13 Jones and Dr. Celia Fisher. I am going to ask 14 each if they would be willing to step up here 15 so I might very ceremoniously present them 16 with a plaque. Perhaps we could start with 17 Dr. Jones and then I want to give each of you 18 the -- Perhaps if I could ask Dr. Jones to 19 come first so each of you can be given 20 individual attention. 21 If I may, I am going to read a 22 letter from Secretary Leavitt or at least a 11 1 portion thereof: 2 "I truly appreciate the level of 3 dedication and loyalty that you, Dr. Nancy L. 4 Jones, have demonstrated in assisting the 5 Departmental efforts to address the many 6 matters that impact this important area of 7 public health and science. 8 "Although your appointment to the 9 Committee is scheduled to end, it is hoped 10 that we may be able to call upon you for 11 further assistance and advice in the future, 12 if need arises." 13 The U.S. Department of Health and 14 Human Services provides this Certificate of 15 Appreciation to Nancy L. Jones, Ph.D., in 16 appreciation for the service you have provided 17 as a member of the Secretary's Advisory 18 Committee on Human Research Protections from 19 January 2003 to January 2007. Signed, Michael 20 O. Leavitt, the Secretary of Health and Human 21 Services. 22 I would like to add my very 12 1 personal appreciation for all of your work. 2 Clap for her. 3 (Applause.) 4 Dr. Fisher, if you would care to 5 join me, it is your turn to be embarrassed in 6 front of your peers here. 7 Dr. Celia B. Fisher, I truly 8 appreciate -- This is from Michael Leavitt, by 9 the way. 10 "I truly appreciate the level of 11 dedication and loyalty that you have 12 demonstrated in assisting the Department's 13 efforts to address the many matters that 14 impact this important area of public health 15 and science. 16 "Although your appointment to the 17 Committee is scheduled to end, it is also 18 hoped that you may be willing to allow us to 19 call upon you for further assistance and 20 advice in the future, if need arises. Michael 21 Leavitt." 22 The U.S. Department of Health and 13 1 Human Services -- I sound like a town crier, 2 don't I? The U.S. Department of Health and 3 Human Services presents this Certificate of 4 Appreciation to Dr. Celia B. Fisher, Ph.D., in 5 appreciation for the services that you have 6 provided as a member of the Secretary's 7 Advisory Committee on Human Research 8 Protections from January 2003 to January 2007. 9 Signed by Michael O. Leavitt, the Secretary of 10 Health and Human Services, and my very 11 personal hand of appreciation. Thank you so 12 much. 13 (Applause.) 14 Okay. Now I wrote a letter to 15 Ernie, to Dr. Prentice, and so did the 16 Secretary. I am not going to read the 17 Secretary's, though. I am going to read mine. 18 Come on up, sir. I won't read everything, 19 because it is a two-page letter. I won't 20 subject you to that, but I will try to read 21 those parts that I think reflect how I am 22 feeling. 14 1 "It is with regret, my personal 2 regret, that I note that you have reached the 3 end of your term as Chair. You have 4 demonstrated on many occasions an effective 5 mix of both diplomacy and patience. You have 6 shown good will, concern, cooperation, 7 support, and quiet humor in dealing with 8 Committee issues." 9 I think he has been an extremely 10 effective leader. 11 "The blend has allowed the 12 Committee to operate effectively and to put 13 forth reachable recommendations to my office 14 in a timely manner. Your inherent ability to 15 distill complex issues and diverse opinions 16 into coherent assessments has enabled SACHRP 17 under your direction, under your leadership, 18 sir, to carry out its mission with great 19 public success. 20 "I believe that the human research 21 enterprise is a better place for the service 22 and dedication that you have provided as 15 1 Chair, and for one of our most important 2 Departmental committees. I thank you over and 3 over and over and over for these four years of 4 public service, and I hope that you will carry 5 with you the sense of our deepest gratitude 6 for your contributions to advancing the cause 7 of human subject protections in the United 8 States and abroad." 9 I signed this one. I'm deeply 10 grateful. 11 (Applause.) 12 It is hard to smile when you are 13 feeling such a sadness, but I have been 14 assured that we will try to reach out to him 15 at the subcommittee level as we move forward. 16 Thanks for your leadership, sir. Thank you. 17 (Applause.) 18 CHAIRMAN PRENTICE: Well, on with 19 the rest of the agenda, but before I do, I 20 would simply like to say that it has been a 21 privilege for me to serve as Chair of SACHRP. 22 The work which we have engaged in over the 16 1 last few years has been challenging, 2 interesting, and rewarding, and a lot of the 3 reward has come from the interaction that I 4 have been able to have with all of the members 5 of SACHRP, former members who are not here -- 6 we miss them -- new members who are here. 7 As you know, Federal Advisory 8 Committees turn over in terms of membership, 9 and that is actually a good thing. 10 I think we have done a lot of good 11 work, and I am going to be talking a little 12 bit about some of that work in a moment, but 13 I do really want to thank everybody for 14 everything that they have done for SACHRP and 15 for protection of human subjects. 16 So you applauded me. I applaud 17 all of you, including the people in the 18 audience who are members of government, the 19 public who also have an interest in this 20 particular area. So thank you for everything. 21 (Applause.) 22 This is our charter, as you know, 17 1 and as the Assistant Secretary said, we are 2 the successor committee to NHRPAC, which was 3 established under Donna Shalala back in 1999. 4 Our initial charter was October 1, 2002, and 5 we have had our charter renewed twice since 6 then, which is probably also remarkable for a 7 Federal Advisory Committee. So that speaks to 8 the work that all of you have done. 9 These are the members of SACHRP, 10 the current members. I want to recognize once 11 again the partnership that SACHRP has with 12 OHRP and all the staff under the leadership of 13 Dr. Schwetz. I really don't think that this 14 Committee could have been as effective as it 15 has been without this partnership. 16 Of course, it wouldn't work at all 17 if it weren't for Cathy Slatinshek. Everybody 18 on SACHRP knows that she is the oil that makes 19 the engine run, keeps us on time, makes sure 20 that everything is done properly, and her 21 assistant, Kelley Booher, who gets us here, 22 gets all of our plane reservations made, hotel 18 1 reservations, etcetera. So thank you, Cathy, 2 and thank you, Kelley. 3 (Applause.) 4 I think this is another unique 5 feature of our Committee, is that we have 6 participation from ex officio members, not 7 only at SACHRP meetings but also on our 8 subcommittee meetings. So I thank all of you 9 from the various Federal agencies for your 10 wisdom and your input to our deliberations. 11 So what are we doing today? Well, 12 I'm not quite done yet with this part, but we 13 are going to go on to have a report of the 14 issues by Dr. Schwetz. We have already taken 15 care of the farewell remarks from Dr. 16 Agwunobi. 17 We will have a break somewhere 18 around 9:30, and then we are going to begin 19 with our report of the Subpart A Subcommittee 20 by Dan Nelson and Felix Gyi. 21 We will break for lunch. We will 22 continue with the Subcommittee report. We 19 1 will have another break. We will have a 2 public comment section, and then we are going 3 to have a discussion and wrap-up somewhere 4 around three o'clock. 5 Now this is something new in my 6 introductions. Since this is the last 7 meeting, I want to remind you of the fact of 8 what we have been able to do since our charter 9 in October of 2002. 10 We have produced recommendations 11 on interpretation and application of Subpart 12 D, additional protections for children, under 13 the Co-Chair leadership of Celia Fisher and 14 Susan Kornetsky. The "C" in red means that 15 their work has been completed, and the last 16 letter of recommendations has either gone to 17 the Secretary or will go forth shortly. 18 Celia, you did great work. thanks 19 very much. 20 We also had a Subcommittee on 21 Subpart C, additional protections for 22 prisoners, and I am sure you recall we had 20 1 what we referred to as the short fix and the 2 long term fix. The short fix was how to 3 interpret Subpart C to resolve problems. 4 Those recommendations have been accepted by 5 the Secretary and handed down to OHRP. 6 The long term fix was to look at 7 how we should amend Subpart C, but before we 8 are going to be able to do that, we needed to 9 understand the current penal environment, what 10 sort of ethical basis should underlie any 11 revision of Subpart C, and consequently, Bern 12 contracted with the IOM to produce a study 13 which was presented to us at the last meeting, 14 and Bern is going to talk more about that in 15 a moment. 16 This is an ongoing activity under 17 the leadership of Dan Nelson and Felix Gyi. 18 Indeed, I suspect it will be a continual 19 subcommittee probably for the next 10 or 15 20 years. There is a lot of work to be done. 21 We did produce recommendations on 22 harmonization of HIPAA and the Common Rule, 21 1 which was sent to the Office of Civil Rights, 2 and Bern has informed me that they are looking 3 at those recommendations, and perhaps we will 4 find some guidance coming forth from OCR at 5 some point in the future. 6 I am sure you will recall that we 7 had a panel looking at various IRB review 8 models, and as a consequence of the panel 9 discussion, we then had a workshop sponsored 10 by AAMC, ASCO, CDC, NIH, that looked at 11 various IRB models, and arising out of that 12 workshop we have a conference which is going 13 to be held, I believe, November 20 or 21 right 14 after the PRIM&R meeting here in Washington 15 on the next step in looking at IRB review 16 models and what sort of guidance should be put 17 forth. 18 Perhaps you recall that the very 19 first meeting that we had of SACHRP we focused 20 on what we considered to be a significant 21 problem, and that is adverse event reporting. 22 As a consequence of a number of panel 22 1 discussions, OHRP has produced draft guidance 2 on adverse event reporting. That has had an 3 opportunity to undergo the public comment 4 period. It has been reviewed that CDC, and it 5 is my understanding that the final draft 6 guidance may be coming out fairly soon. 7 OHRP is also in the process of 8 producing draft guidance on the definition of 9 research. We had a panel on what is research, 10 and for those of you who were there, I'm sure 11 you recall that there was a lot of 12 disagreement as to what was and what was not 13 research. So we are looking forward to that 14 draft guidance, and have an opportunity to 15 comment on it, particularly having our Subpart 16 A Subcommittee look at that draft guidance. 17 This is our latest endeavor to 18 respond to the Secretary's charge. We have 19 appointed or are in the process of appointing 20 a Subcommittee on Research with the 21 Decisionally Impaired. I think this is 22 something that was long overdue, and I am 23 1 absolutely delighted that we are going to have 2 a subcommittee. 3 We have identified roughly half of 4 the membership for that particular 5 subcommittee, which will be co-chaired by 6 David Strauss. 7 We had a panel on the involvement 8 of institutional officials in human research 9 protection programs, and arising out of that 10 panel is an initiative by Bern and OHRP to 11 promote greater involvement of IOs in the 12 human research protection enterprise. That 13 work is ongoing, and perhaps Bern might 14 mention a few things about that particular 15 initiative. 16 So I think we've done a lot over 17 the last few years, and as I have often said 18 before, I don't deserve the credit, because I 19 really didn't do the work. All I do is come 20 to meetings here and try to keep things 21 ongoing and on focus. The credit belongs to 22 the SACHRP members and the Subcommittee 24 1 members. 2 Now to get back to what we have to 3 do in terms of technicalities, I would be 4 delighted to entertain a motion for approval 5 of the minutes. 6 DR. BOTKIN: So move. 7 CHAIRMAN PRENTICE: Thank you very 8 much. Is there a second? Wake up, wake up. 9 DR. FISHER: Second. 10 CHAIRMAN PRENTICE: There we go. 11 We got two seconds. All right. Great. Any 12 further discussion? 13 Hearing none, all those in favor? 14 Any opposed? Any abstentions? Wonderful. 15 Next, report on the issues. Bern, 16 would you like to do it at your table or come 17 up here? 18 DR. SCHWETZ: You want me to come 19 up there? 20 CHAIRMAN PRENTICE: Okay. 21 DR. GENEL: Mr. Chairman, will we 22 be able to get a copy of your presentation for 25 1 those of us who are new to the Committee, so 2 we can appreciate what has been accomplished 3 before we came on? 4 CHAIRMAN PRENTICE: You mean a 5 copy of the PowerPoint? 6 DR. GENEL: Yes. 7 CHAIRMAN PRENTICE: Absolutely. 8 You would like to have a copy of the 9 PowerPoint? 10 DR. GENEL: Not the one that you 11 just provided, I believe. 12 CHAIRMAN PRENTICE: What is it you 13 are asking for? 14 DR. GENEL: The summary of the 15 SACHRP accomplishments. 16 CHAIRMAN PRENTICE: It will be in 17 the transcript, what I just said, and you will 18 have access to that transcript, of course. 19 DR. SCHWETZ: Thank you, Ernie. 20 Good morning to all of you, and for those of 21 you who didn't need to be here today, thank 22 you for being here, as well as to thank all of 26 1 the SACHRP members and the ex officios. 2 There are several things that I 3 want to update you on, some of which Ernie has 4 already flagged, the first one being where we 5 are relative to the National IRB conference 6 that I have mentioned before. 7 This is the conference that we are 8 going to hold on November 20 and 21st at the 9 Marriott Wardman Park Hotel, where the theme 10 of the conference is "Alternatives to Local 11 IRBs," and the underlying issue was one that 12 came to SACHRP a couple of years ago asking 13 the question on behalf of ASCO and the 14 oncology research community about why central 15 IRBs aren't used more widely than they are. 16 We turned that question into a 17 workshop that we had last year to look at 18 alternatives to local IRBs, and now the 19 national conference based on a recommendation 20 from SACHRP during the past year that we would 21 follow up that workshop with a national 22 conference to look at this in greater depth, 27 1 but with the larger audience that was open to 2 the public. 3 So we are going to be talking 4 about issues of liability, regulatory and 5 legal; cost; the timeliness of reviews; shared 6 authority and responsibilities; the quality of 7 review; and local context, among other things, 8 as a way of comparing the different models of 9 IRBs that are used. 10 I am pleased to say that we 11 already have over 300 people registered for 12 this meeting, and we are two weeks away. I 13 had anticipated that, if we had an audience of 14 400 people, that would be a pretty large 15 audience. Well, we are already over 300. So 16 I suspect we will be something over 400. 17 For those of you who can influence 18 who might still sign up for this meeting, the 19 people that we really need to come to this 20 conference are those who make the decision 21 about what IRB model they use in their 22 institutions. 28 1 So I am not saying that we don't 2 need IRB members there. We do, but the people 3 whom we really need to have are the 4 institutional officials, the institutional 5 attorneys, the research deans, and others in 6 the institution who make that decision that, 7 yes, we will or, no, we will not use an 8 alternative for the local IRB. But we 9 certainly want the IRB folks to be there, and 10 investigators, research subjects, advocates, 11 and others who are part of this larger 12 enterprise to help those people who make that 13 decision to be better informed and more 14 innovative as they think about what model of 15 IRB to use for the particular research program 16 that you have and the types of protocols that 17 you review. 18 So on November 20-21, right after 19 the PRIM&R meeting, and I hope that as many of 20 you as possible will be there. 21 Ernie talked about the 22 recommendations on research involving 29 1 prisoners. We had the IOM report last time at 2 the last meeting. Since then, our folks in 3 OHRP have been evaluating all the 4 recommendations from the IOM report, as well 5 as the recommendations that came from you, 6 SACHRP, with the first evaluation of what of 7 these recommendations really apply to OHRP 8 versus which apply to the Department versus 9 which apply to Congress. 10 From the standpoint of those that 11 applied to us, what are the things that we can 12 do by guidance or what are the things that we 13 can do by rulemaking instead? 14 So we have had those discussions 15 and, as Dr. Agwunobi said, we are planning a 16 meeting with him to brief him on what is in 17 the IOM report and what is in your 18 recommendations, and our suggestions for how 19 we might follow up on this. 20 So I am assuming that we will get 21 that meeting with him sometime in the near 22 future, and that will determine the things 30 1 that we are going to handle within OHRP. 2 The recommendations from the 3 Subcommittee on Research Involving Children is 4 kind of in the same category. Now that that 5 subcommittee has completed its task, we have 6 the recommendations, and there are about 40 7 recommendations that are going to go to the 8 Secretary, to come back to us. 9 The situation with that is 10 somewhat like those involving prisoners in 11 that we have evaluated those to determine what 12 are the things that we can do by guidance, and 13 what are the things that would have to have 14 some mechanism other than guidance, some 15 rulemaking effort to be able to deal with the 16 recommendations. 17 We are going to proceed as soon as 18 we reach agreement internally on how we are 19 going to write this. We are looking to 20 developing a package of guidance that will 21 include the recommendations that you have made 22 to us. 31 1 I am very pleased to say -- and 2 you have been updated on this a couple of 3 times -- where we are relative to our guidance 4 on anticipated problems in adverse events. We 5 are at the final stages of making revisions to 6 that, and we are hoping that we will get this 7 out in its final form yet in 2006, so sometime 8 in the next couple of months. So we are close 9 on that one. 10 We have talked from time to time 11 about the research at international sites, and 12 I am pleased to say that we have an updated 13 compilation of the guidance and regulations 14 from 76 different countries and from several 15 international organizations that have 16 guidance. 17 So that again is an expanded set 18 of information that is available to any of you 19 who have questions about what is it like to do 20 research in whatever the country is. So if 21 there is something, it is in that set of 22 guidances available on our website. 32 1 You are aware that we have been 2 writing Frequently Asked Questions, the 3 answers to Frequently Asked Questions, and 4 putting them up on our website. I would just 5 say that access to that is now easier, because 6 it is accessible directly from our website, 7 and we have added a new set of answers to 8 Frequently Asked Questions about investigator 9 responsibilities. So that is the newest entry 10 into that list of FAQs. 11 I do want to comment on the 12 success, Ernie, that I have had in reaching 13 out to institutional officials and signatory 14 officials of the FWA. I approached this quite 15 a few months ago as something that I wanted to 16 follow up on, because of the difficulty I had 17 reaching investigators. 18 It is easy for us to reach the IRB 19 community, because when we say there is going 20 to be a meeting, you come. But the 21 investigators don't. They have a different 22 set of pressures on them and a different sense 33 1 of responsibility from the standpoint of 2 listening to OHRP. 3 So I realized pretty soon on that 4 I wasn't going to reach investigators by 5 asking for meetings with investigators, except 6 those who already are fully appreciative of 7 what their needs are relative to human subject 8 protection. But I realized that I could reach 9 them through their institutional officials and 10 the signatory officials to the FWAs. 11 So I started, one by one, tacking 12 meetings on with institutional officials to 13 other OHRP meetings or other gatherings. I am 14 happy to say that now I am at the stage where 15 institutions and regions are approaching me 16 and saying we would like to invite you to have 17 a meeting with the institutional officials of 18 wherever the area is. 19 Just last week, I had a meeting 20 with the institutional officials from the 21 state of Michigan, and we are now getting 22 phone calls from people saying we would like 34 1 to schedule a meeting for Dr. Schwetz to be 2 able to meet with the institutional officials 3 in whatever the region is. 4 So I think I'm beginning to reach 5 an audience that, as I impress on them their 6 role in the education and training of 7 investigators and their responsibility for the 8 culture of research that goes on in their 9 institutions, that I am feeling good about 10 reaching -- about having the institutional 11 officials want to meet with me and learn how 12 they can do their job better, and I am 13 learning how OHRP can be of more help to the 14 institutional officials. So I feel good about 15 that. 16 Let me talk a little bit about 17 Special Government Employees. For those of 18 you who aren't familiar with that phrase, it 19 is a special phrase in the government that 20 identifies how, for example, Federal advisory 21 committee meetings, members, are classified 22 within the government. They are actually a 35 1 form of government employee referred to as 2 Special Government Employees. 3 In the past, that has just been a 4 phrase for me as I have worked with various 5 Federal advisory committees, but as I thought 6 about what this meeting means today, it took 7 on a different meaning, a different sense, as 8 we have three members who are coming off 9 SACHRP. 10 So let me talk first about Celia 11 and Nancy. Nancy, you have always been a 12 voice of reason for us as we have had 13 discussions on SACHRP, and you have helped to 14 keep the discussions in bounds or you have 15 helped to expand the bounds a little bit as it 16 needed to be expanded. 17 You didn't just weigh in on things 18 that were your agenda. You were engaged on 19 all the issues that were under discussion by 20 SACHRP, and you certainly have always been 21 worth listening to, whenever you had something 22 to say, whatever the issue was; and even if it 36 1 was just we need to think about this a little 2 bit more before we would make a decision, 3 that has been helpful. So, Nancy, I really 4 appreciate the help that you have been to us 5 by being on SACHRP for these four years. 6 Celia, you have also been a 7 contributor on all the issues, and you have 8 voiced your opinions. You have given 9 information. You have been very helpful to us 10 as you have deliberated on the wide variety of 11 issues that SACHRP has taken on, and I would 12 voice what others have said, that your role as 13 the Co-Chair of the Subcommittee on Research 14 Involving Children has been a major 15 contribution to SACHRP, and beyond. 16 The work product will be valuable, 17 highly important to the broad research 18 community, and what you accomplished by your 19 personal investment in all of the work that 20 you did in co-chairing this Subcommittee is 21 very impressive to me, and we all owe you a 22 special thanks for the hard work that you did 37 1 to make the Subcommittee productive, and when 2 subcommittees are productive, so is SACHRP. 3 So thank you very much for your role in that. 4 So then when I think of Celia and 5 Nancy as being Special Government Employees, 6 then when I switch to Ernie, I think there 7 must be a category of Very Special Government 8 Employees, and it begins to sound like cognac. 9 But it wasn't intended to be that. 10 Nonetheless, Ernie through his 25 11 years of experience in the IRB community as an 12 IRB chair certainly had an agenda of his own, 13 and we benefitted from that; but he didn't 14 impose his agenda on us. He knew what the 15 important things were, but he worked with me, 16 and he worked with the rest of us to develop 17 an agenda that we came to know as the agenda 18 for SACHRP, focused on the IRB community, but 19 also focused on human subjects. 20 I think Ernie has given us 21 excellent advice as he has moved us along in 22 this four years on the issues that SACHRP 38 1 should be paying attention to. 2 The leadership to be able to make 3 the subcommittees productive and relevant, as 4 they have moved along, has been a particular 5 skill of Ernie's. One of the things, Ernie, 6 that I think is a measure of the success to 7 you is that there has been an image of SACHRP 8 that has been created that, as we, for 9 example, advertise in the Federal Register 10 that we announce that we need new members for 11 SACHRP, and as we seek members of 12 subcommittees, I think Ernie has been 13 instrumental in developing a reputation for 14 SACHRP that people not only volunteer, but 15 they aspire to be on SACHRP, and that's not 16 common among Federal advisory committees. 17 Most people wait to have their arm 18 twisted and, if there isn't any other choice, 19 they say, yes, I will. But it is often with 20 reluctance. Now we have people who definitely 21 want to be on SACHRP because of what Ernie has 22 contributed, but also what all of you have 39 1 created as the image of SACHRP. 2 You have developed four sets of 3 recommendations, the last of which is going in 4 at this point in time with all of the 5 children's recommendations. So the 6 productivity of SACHRP is certainly there and 7 measurable. 8 The amount of time and energy that 9 Ernie has committed to SACHRP is also 10 something that is very unusual among chairs of 11 -- members of a Federal advisory committee and 12 certainly chairs of an advisory committee, and 13 we have benefitted greatly by Ernie's 14 willingness to take the time to participate in 15 subcommittee meetings and all of the hours and 16 hours of communication that we have had 17 between SACHRP meetings between Ernie and us 18 to make sure things are moving and to talk 19 about directions and to just talk about how we 20 could make SACHRP better and to make sure that 21 we are focused on the right issues. 22 So, Ernie, I have learned a lot 40 1 being able to work with you and in the context 2 of the rest of SACHRP. A lot of us have 3 benefitted from what has happened in SACHRP, 4 and it isn't just OHRP and FDA and the other 5 agencies that are represented here today, but 6 certainly the IRB community and, I think, the 7 greatest impact long term is what this 8 translate into in terms of human subject 9 protection. 10 So it isn't our goal to just have 11 IRB members more informed. That is just a way 12 to get to what our real job is, to make sure 13 that subjects are protected better, and you 14 have certainly helped us accomplish that. 15 Now being the young and 16 influential person that Ernie is, we're not 17 saying goodbye to him, and I am certain that 18 he will continue to have a significant impact 19 on the protection of human subjects through a 20 variety of avenues that he has always been 21 engaged in, and we would certainly welcome 22 that we would have a role for you within the 41 1 SACHRP community as well, Ernie, to continue 2 to have your influence. 3 So I want to thank you, Ernie, for 4 the contributions that you have made to SACHRP 5 and, for me personally, for the friend you 6 have been while you have done it. So thank 7 you. 8 (Applause.) 9 There is something else that I 10 want Ernie to receive. When I came into OHRP 11 a few years ago, I wanted to create something 12 that -- It was kind of a Director's award, 13 but an award from OHRP that could be given to 14 people who had played highly significant roles 15 in the protection of human subjects, and we 16 first used this award -- We first gave this 17 award to the members of the National 18 Commission and those who helped the National 19 Commission members when we celebrated the 25th 20 anniversary of the Belmont Report. 21 We haven't given this award to 22 anybody since then. So, Ernie, you get the 42 1 first one beyond the National Commission, and 2 I'm hoping that this is something that you 3 will display wherever you choose to display 4 it. 5 (Applause.) 6 CHAIRMAN PRENTICE: Well, needless 7 to say, I'm obviously deeply honored. I am 8 going to have to out and buy another suitcase 9 to carry back all of these awards and plaques. 10 I mentioned earlier that I think 11 the success of SACHRP is due to, obviously, 12 all the hard work of the members, subcommittee 13 members, but also the partnership that we have 14 had with OHRP, and when I talk about that 15 partnership, I obviously include Bern as 16 Director of OHRP and its leader, but I also 17 include all of the OHRP staff. 18 For those of you on SACHRP, of 19 course, you know that OHRP staff have been 20 assigned as expert liaisons to all of the 21 subcommittees. They work hand in hand with 22 the co-chairs of the subcommittees. 43 1 So I would really like to 2 recognize their contribution to our success 3 and our work product. So if you don't mind, 4 the OHRP staff that are here -- I see you 5 around -- would you please stand up and be 6 recognized? 7 (Applause.) 8 Thank you very much. 9 All right, are there any questions 10 for Bern, myself, before we take a brief break 11 and allow our two co-chairs of Subpart A 12 Subcommittee to get prepared? Twelve minutes. 13 then we will be back and get started again. 14 (Whereupon, the foregoing matter 15 went off the record at 9:19 a.m. and went back 16 on the record at 9:48 a.m.) 17 CHAIRMAN PRENTICE: Okay, folks, 18 we are about ready to get going again, if 19 people would assume their seats. 20 Now we are going to consider the 21 report from the Subpart A Subcommittee who 22 have been working very hard on various aspects 44 1 of Subpart A in the common rule, and we will 2 continue until lunch. We will adjourn then 3 and continue again in the afternoon. 4 So, Dan, Felix, are you ready? 5 MR. NELSON: Thank you, Ernie. 6 Felix just whispered to me that that was the 7 longest 12 minute break he had ever seen, 8 which I attribute to the first SACHRP meeting 9 held in a penthouse with views of the city and 10 the fall colors. But thank you for returning 11 your attention to us, and we will do what we 12 can to rivet your attention up here, 13 hopefully. 14 Let me, before we go on, add our 15 congratulations and thanks to Ernie and Nancy 16 and Celia for the many contributions they have 17 made and the support they have given us in our 18 efforts. 19 Today's presentation will follow 20 much the same format that you have seen in the 21 past: A quick overview of our charge and 22 membership, and then presenting what we hope 45 1 are our final recommendations on the two 2 topics of continuing review and expedited 3 review. 4 Then we will move to something 5 quite different in concept and format, and 6 present an analytical framework for minimal 7 risk, which is something our subcommittee has 8 been wrestling with from the start as we've 9 looked at these other areas, because that 10 definition is so intertwined with so many 11 other aspects of Subpart A, the common rule. 12 Finally, we would like to close 13 with a request for our marching orders for 14 next topics, hoping that the preceding 15 discussion has led to resolution of these few 16 loose ends that we have from preceding 17 presentations. 18 So our charge to the Subcommittee 19 from our Chair: Review and assess all 20 provisions of Subpart A, 45 C.F.R. 46, and 21 associated relevant OHRP guidance documents, 22 and based on this review and assessment, 46 1 develop recommendations for consideration by 2 SACHRP in three categories in, I guess, if you 3 will, increasing difficulty, area of 4 difficulty, interpretation of specific Subpart 5 A provisions, development of new or 6 modification of existing OHRP guidance or 7 possible revisions to Subpart. 8 We have been putting forth 9 recommendations that really fall in all three 10 of those -- three levels of recommendation. 11 The charge to the Subcommittee: 12 Our goals are to enhance protection of human 13 subjects, to reduce regulatory burdens that do 14 not contribute meaningfully to the protection 15 of human subjects, and to promote 16 scientifically and ethically valid research. 17 Those of you in this audience have 18 heard me say each and every time that we 19 viewed these as not mutually exclusive goals, 20 but as, in fact, compatible goals. I keep 21 repeating that. I feel like, when you give a 22 talk on informed consent, you get to the part 47 1 where you say informed consent is not just a 2 form, it's a process and the entire 3 congregation recites it in harmony with you, 4 it has almost become a mantra for us in these 5 presentations. but I think it is worth 6 repeating, because, if not in this room, out 7 in the broader community there are certainly 8 practices and practitioners who view these as 9 mutually exclusive goals. 10 There is a sense that more 11 regulatory burden or more regulation must 12 necessarily protect subjects more or, 13 conversely, that protection of subjects 14 demands that we not push the limits in a 15 scientific capacity. I think we see all of 16 these going ahead as compatible goals. 17 Our Subcommittee membership: Some 18 in the room today, Gary Chadwick from 19 Rochester; Bruce Gordon from Nebraska; Felix 20 to my right, my co-chair; Isaac Hopkins from 21 New Jersey; Nancy, who is just stepping off; 22 and Moira Keene from Minnesota; Susan 48 1 Kornetsky from Boston; Gigi McMillan from Los 2 Angeles; myself from the University of North 3 Carolina; Lorna Rhodes from Washington who I 4 have highlighted here. 5 As we did previously when Tom 6 Puglisi stepped off of our board, we wanted to 7 recognize Lorna, who is an anthropologist and 8 has had stellar contributions as we considered 9 social and behavioral issues, and because of 10 personal circumstances has needed to step 11 aside and focus on duties back home, which we 12 understand but appreciate and wanted to 13 recognize her contributions one last time, and 14 we will be looking, I hope, with SACHRP's help 15 to identify additional expertise in the area 16 of the social and behavioral sciences as we go 17 ahead. 18 Ada Sue Selwitz from Kentucky, and 19 David Strauss from New York City. And again 20 with excellent contributions from the ex 21 officios and OHRP, as Ernie previously noted. 22 Our growing list of Subcommittee 49 1 meetings, and I have highlighted the last two 2 which were held via teleconference. 3 Scheduling being what it was and busy 4 calendars, we were unable to get everybody 5 together for another on-site Subcommittee 6 meeting, but we did hold two lengthy 7 teleconferences in September and October in 8 preparation, so that we could be in position 9 to bring you these final recommendations 10 today. 11 Just a reminder of those previous 12 installments from our recommendations. We 13 have previously presented to you 14 recommendations in the area of continuing 15 review. Nine were approved in November of 16 last year. Six were approved in March earlier 17 this year, and in the area of expedited 18 review, five were approved in March 13th, and 19 then it may appear that we hit the brick wall 20 last July. We left with zero approved, which 21 I've documented here, but we are bringing back 22 -- Many of these were approved, in fact, in 50 1 concept with a request that we reconsider and 2 fine tune a bit and bring back for your final 3 approval today, which we are happy to do, and 4 that is what you will see in the next few 5 slides, and they are relatively few slides. 6 Taking a different tack, you will 7 remember -- the members will remember, last 8 July we spent quite a bit of time sketching 9 out the background in these areas in terms of 10 regulatory and ethical construct, and the 11 problems in applying the regulations in these 12 areas, and then re-reviewing the 13 recommendations that you had previously 14 approved. 15 We are cutting to the chase, if 16 you will, today. I was thanked after the fact 17 for laying that background out before, but we 18 won't repeat that today, having done that 19 previously. So we are going to truncate the 20 background and just get right in short order 21 to the final recommendation in this area. 22 By way of just a little bit of 51 1 background, there are these regulations in 2 Subpart A that are relevant to the area of 3 continuing review. Written procedures are 4 required. This guides the conduct of convened 5 meetings as well as expedited review, or ties 6 into. 7 There is one section which I will 8 explicate on the next slide that is 9 specifically relevant to IRB review -- or to 10 continuing review. It, of course, ties into 11 expedited review, criteria for IRB approval, 12 and informed consent. 13 So it has broad reaching 14 implications throughout Subpart A, but this is 15 the single regulatory citation that addresses 16 continuing review with any detail, and reads 17 in its entirety that an IRB shall conduct 18 continuing review of research covered by this 19 policy at intervals appropriate to the degree 20 of risk, but not less than once per year, and 21 shall have the authority to observe or a have 22 a third party observe the consent process and 52 1 the research. 2 As we have noted previously, 3 predictably, this rather sparse regulation has 4 been applied in variable ways across the 5 country, across the world, as IRBs seek to 6 employ this, and the guidance, we feel, has 7 needed some updating. 8 So our working assumptions as we 9 viewed this area are that continuing review 10 plays a central, often undervalued role in the 11 IRB process, but the practices that do not 12 demonstrable enhance the safe and ethical 13 conduct of research diminish overall human 14 subject protections. 15 So with that truncated background, 16 I will turn to the single remaining issue of 17 concern in the area of continuing review, 18 again reminding you that all of our other 19 recommendations in this area have been 20 presented to and approved by SACHRP. 21 This arose under the question of 22 how should temporary lapses in approval at the 53 1 time of continuing review be handled. This is 2 the existing OHRP guidance from the latest 3 version of this guidance, from July of 2002. 4 It reads: If an investigator has failed to 5 provide continuing review information to the 6 IRB or the IRB has not reviewed and approved 7 the research study by the continuing review 8 date specified by the IRB, the research must 9 stop unless the IRB finds that it is in the 10 best interest of individual subjects to 11 continue participating in the research 12 interventions or interactions. Enrollment of 13 new subjects cannot occur after the expiration 14 of IRB approval. 15 We previously brought forward and 16 SACHRP has approved sort of half of our 17 recommendation in this area, and that would be 18 this one, which was approved, actually, last 19 November. 20 So on the matter of continued 21 participation of subjects during temporary 22 lapses, we recommended, and was approved, that 54 1 wording in current guidance that refers to 2 individual requests should be revised to 3 clarify that approval of a general request for 4 all research subjects to continue in the 5 research during the review process is 6 acceptable. 7 Again, already approved, and I 8 present I there just because it comes as a 9 couplet with the unapproved portion, which is 10 here for your consideration today. Again, I 11 know we presented this previously, and there 12 were some logical and reasonable questions 13 that were raised on this, but endorsed in 14 principle by you in July. 15 So on the matter of suspending all 16 study activities when continuing review is 17 underway, we would recommend that OHRP should 18 modify guidance on continuing review so that: 19 When the study has been reviewed by the IRB 20 either at a convened meeting or through an 21 expedited review process, as appropriate, and 22 the IRB finds that there are no substantive 55 1 concerns that impact human subject 2 protections, suspension of all research 3 activity is not required when the expiration 4 date passes, provided that IRB review is 5 completed within 30 days past that expiration 6 date. 7 I have highlighted there in orange 8 the parts that were a matter of some 9 discussion at the last meeting, and request 10 for a slight wording modifications, just to 11 clarify this. In particular, the second of 12 those, I think, we previously referred to 13 automatic study suspension, and it was not 14 exactly clear what was meant by that. This 15 was a suggestion that would clarify it. 16 So with that, we would ask for 17 your discussion and, hopefully, your approval. 18 CHAIRMAN PRENTICE: All right, the 19 recommendation is open for discussion, 20 questions, clarifications. Hearing none, let 21 me ask a question then. 22 Substantive concerns that impact 56 1 human subject protection -- What does that 2 mean exactly? 3 MR. NELSON: I think what we would 4 like it to mean is that, again, review is 5 already underway as the predicate here, and 6 that there are, as we often see, non- 7 substantive issues that may come up, consent 8 form updates, small items, clarifications, but 9 nothing that would impact in any meaningful 10 way on the human subject safety aspects, and 11 that if those are -- In other words, if it is 12 largely bookkeeping or things that, in the 13 judgment of the IRB, can easily be reconciled, 14 those would not then automatically translate 15 into a suspension of all research, as the 16 current practice is understood. 17 If I understand where you question 18 is going, substantive is, obviously, a 19 subjective term, and it is going to be left to 20 the discretion of the IRB, like so many other 21 things are in this area. But that was the 22 general point we are trying to get across. 57 1 Felix, do you want to add to that? 2 DR. GYI: A point to remember is 3 that expedited review in this setting, as in 4 other settings, is not review-like. I mean, 5 it is -- You know, we have used that phrase 6 before, that it carries the same weight and 7 authority of a full convened IRB under the 8 regulations. 9 So if we are thinking about 10 substantive in the context of an expedited 11 review and thinking that there might be some 12 things that would fall through the cracks, 13 that was not the intention of the 14 Subcommittee's recommendation. So I want to 15 make sure that the committee is aware of that 16 level of authority that is given to the IRB. 17 CHAIRMAN PRENTICE: So you are 18 comfortable leaving this subjective judgment 19 to the IRB without any further guidance? That 20 is kind of where I am going on this particular 21 issue, without any examples, for example? 22 DR. FISHER: Ernie, can I ask a 58 1 question? In terms of the process, this is 2 really about whether or not the paperwork has 3 been completed, not whether or not they have 4 actually looked at -- is that true? 5 MR. NELSON: That is correct. In 6 fact, the paperwork has been submitted, if you 7 will, the progress report, the required 8 materials, and review has begun. But there 9 are issues that have been identified that are 10 going to take a little back and forth. Again, 11 maybe examples would be helpful, whether or 12 not we embed them in the recommendation or 13 not. 14 If it is, you know, we have 15 changed our consent form templates and you 16 need to revise it, or you had a co- 17 investigator leave and they need to be removed 18 from the application and the consent form, 19 things like this that need cleaning up, we 20 would view as not worth stopping everything 21 cold in its tracks, as opposed to here's a 22 whole set of adverse events or unanticipated 59 1 problems that we are concerned about. That's 2 not what we are talking about. There, we 3 would explain. 4 DR. FISHER: Right. And I am very 5 much for this recommendation. I am just 6 wondering, given Ernie's comment, whether it 7 can be operationalized better with respect to 8 no substantial deviation from what the IRB had 9 approved, you know, something in that 10 language; because that is really saying what 11 you are saying, that the harms have not 12 increased. You know, the risk/benefit balance 13 has not changed. 14 There might have been some minor 15 modification in procedure that would require 16 more -- you know, some shift in the 17 explanation. But I am just wondering if you 18 could ground it in the prior IRB review, and 19 that might help the language. 20 MR. NELSON: I think the only 21 concern I, at least personally, might have 22 with that is it seems to point to deviations, 60 1 violations, where we are talking about more 2 than that. We are talking about any 3 substantive concerns. 4 Adverse events that have arise 5 might not have anything to do with deviations. 6 They have happened, and you want to know about 7 it, but that wouldn't necessarily be captured 8 in this rephrasing. So a rephrasing is 9 certainly welcome, but I'm not sure if that 10 one gets us any closer to operationalizing 11 this than the current one. 12 CHAIRMAN PRENTICE: How about 13 this: Inserting after "there are no 14 substantive concerns:" In terms of the 15 risk/benefit relationship or the informed 16 consent that impact human subject protections. 17 That way, if you take into 18 consideration the risk/benefit relationship, 19 that encompasses everything pretty much. 20 MR. NELSON: And I would say that 21 gets to what we are after. I would only ask 22 if there is anything that it is excluding. 61 1 That's a good suggestion. Is there danger 2 that we are excluding something else that we 3 might consider a substantive concern that 4 doesn't get to risk/benefit or informed 5 consent? 6 CHAIRMAN PRENTICE: It seems to me 7 that it almost encompasses pretty much 8 everything, unless I am missing something. 9 DR. GYI: That clarification still 10 puts the responsibility and onus on the IRB, 11 if I am hearing you correctly. 12 CHAIRMAN PRENTICE: That's 13 correct. 14 DR. GYI: Not on the investigator. 15 CHAIRMAN PRENTICE: That's 16 correct. 17 DR. GYI: So the intention of this 18 particular section was to give IRB more 19 guidance in terms of what they can and cannot 20 do as opposed to giving the latitude to the 21 investigator to say that they have latitude to 22 submit a paper. 62 1 CHAIRMAN PRENTICE: This doesn't - 2 - This really doesn't pertain to the 3 investigator. This is at the time of IRB 4 review. Whether it is full board or 5 expedited, the IRB is in a process of carrying 6 out the continuing review, and as Dan 7 indicated, sometimes you find some I's need to 8 be dotted, some T's need to be crossed on a 9 consent document. That doesn't impact human 10 subject protection. Yet you are required to 11 halt all research activities. 12 This just simply frames what we 13 mean by substantive concerns, and if you look 14 at all of the approval criteria in 46.111, I 15 think that you can probably fit most of the 16 approval criteria, if not all of it, one way 17 or another, into those two categories. 18 Confidentiality, you know, 19 safeguards of privacy -- that risk/benefit 20 relationship; minimization of risk, 21 risk/benefit relationship; acceptable 22 risk/benefit relationship. That's a 63 1 requirement. Protection of vulnerable 2 subjects, either risk/benefit relationship or 3 informed consent. 4 So I think that it offers a little 5 bit more clarification, rather than leaving it 6 open. I mean, what do we mean by concerns? 7 Nancy, I saw your hand up first. 8 DR. JONES: What about at the end 9 of it, if you are going to -- No substantive 10 concerns that impact human subject protection 11 such as altering the risk/benefit ratio, or 12 something like that. 13 My one concern with putting in 14 informed consent is, if somebody was going to 15 be a literalist, would they then say, if we've 16 changed our insurance carrier and we ask the 17 investigator to change the insurance carrier 18 on their form, that would be in the informed 19 consent, and -- 20 CHAIRMAN PRENTICE: But that is 21 not a substantive concern. You would let the 22 IRB make that judgment as to when it is and 64 1 when it is not. 2 DR. JONES: Okay. 3 CHAIRMAN PRENTICE: Celia? 4 DR. FISHER: I was thinking, based 5 on Dan's really good point about the 6 anticipated and unanticipated harms -- and I 7 do agree with Nancy that, as soon as we start 8 putting in risk/benefit, informed consent, it 9 may be what else are we missing. 10 So I was wondering whether 11 something like "and the IRB finds that there 12 are no substantive deviations from procedures 13 initially approved or any anticipated or 14 unanticipated harms of substantial concern." 15 CHAIRMAN PRENTICE: I think you 16 are getting too narrow. 17 DR. FISHER: Okay. 18 CHAIRMAN PRENTICE: Particularly, 19 relative to deviations. If you want to extend 20 Nancy's suggestion and say there are no 21 substantive concerns such as, then you could 22 say "such as a negative impact on the 65 1 risk/benefit relationship" or something 2 relative to the informed consent. You could 3 say "such as," if you feel more comfortable 4 with putting it at the end rather than 5 inserting it right after "concerns." 6 DR. JONES: Should we have just 7 "no substantive concerns" or do you want to 8 keep the intent of "that impact human subject 9 protection" or is that -- When you think of 10 concerns, it is the concern of impacting human 11 subject protection. I don't know. 12 MR. NELSON: Yes, I think the 13 reason that impact human subject protections - 14 - what we were trying to say there is what you 15 are all trying to help us explicate, that 16 there may be substantive concerns in other 17 areas, but if it doesn't get to the root of 18 what we are after, then let's not stop and -- 19 I don't know if this is a useful analogy, but 20 you know, IRBs are faced with a similar 21 decision when it comes to interpreting what 22 constitutes a minor change to previously 66 1 approved research. 2 Can you approve it by expedited 3 review? Do you take it to the full board? 4 And there isn't much to go on there. What 5 does minor mean? 6 Most of us have operationalized 7 that as, well, if it doesn't negatively impact 8 on the risk/benefit ratio, we can handle that 9 by expedited review. Again, I don't know if 10 that is a useful benchmark, but that is the 11 gestalt of where we are trying to go with 12 this. 13 ACTING CHAIRMAN HARRIS: Sam? 14 DR. TILDEN: I probably shouldn't 15 say this, but I wonder if just taking that 16 out, "If the IRB finds there are no 17 substantive concerns that impact human 18 subjects protections," and just say that OHRP 19 should modify the guidance on continuing 20 review to allow IRBs to not suspend all 21 research activity, number one. I think that 22 is what we are trying to get across. Right? 67 1 Then maybe add a second sentence 2 saying, you know, OHRP should consider 3 guidance or criteria for when suspensions are 4 appropriate or not, based on these substantive 5 concerns. 6 So that I think we are trying to 7 get at the fact -- I don't know how all IRBs 8 work, but we have something called minor 9 modifications, etcetera. To be a minor 10 modification, you have to declare what they 11 are, and that most IRBs work under, and they 12 go to these clerical things, administrative 13 things. 14 The IRB has really done the 15 review, but the investigator has to respond 16 regarding certain things. It is not going to 17 change the risk/benefit ratio. It is not 18 going to substantively, as you say, or 19 materially alter the consent form. They just 20 got to get it done. 21 If that is the case, then why halt 22 the research? That is what we are trying to 68 1 get at, but I'm wondering if linking this to 2 the IRB finding in the initial paragraph might 3 -- as we are getting hung up on, if we could 4 state what we would really like to see, that 5 all activity doesn't have to be suspended and 6 that some criteria should be defined, as just 7 a second sentence to make that piece work. 8 If we don't have anymore concrete 9 advice to give, maybe not try to generate it. 10 MR. NELSON: I guess I have 11 conflicting thoughts in response to that. One 12 is that, no matter what we approve here, this 13 still has to be placed into a letter to the 14 Secretary and translated to OHRP and go 15 through further rounds of editing, no doubt, 16 beyond what we are doing today, which might 17 argue in favor of making sure we get the 18 concept down clearly and then passing it up -- 19 passing it through that pipeline. 20 The counter-argument -- or the 21 other thought, which does take me in a 22 different direction, is that I think in 69 1 general we would like to give OHRP as much of 2 a clue as we can with as carefully crafted 3 wording as we can what we are after, without 4 expectation that it is going to be taken 5 verbatim. 6 So if we leave it too open-ended, 7 in other words, we are maybe just asking for 8 a different variation of what we see as a 9 problem right now. 10 So I have conflicting thoughts, 11 but I appreciate what you are saying, Sam, and 12 if we can figure out a way to pass this ahead. 13 CHAIRMAN PRENTICE: James? 14 DR. POWELL: Well, the only thing 15 I'm thinking about is I don't really see -- I 16 happen to like the language that you 17 mentioned, Ernie, with respect to benefit/risk 18 and informed consent, in that why would -- I 19 don't understand the concern for taking out of 20 the IRB's hand that kind of judgment, given 21 all the other evaluations they are doing. 22 To me, it makes sense to add the 70 1 language that you put in, Ernie, and let it go 2 at that. 3 CHAIRMAN PRENTICE: Okay. Let me 4 restate a slightly modified version of 5 suggested language. After substantive 6 concerns, in terms of the risk/benefit 7 relationship, informed consent or other 8 substantive concerns that impact human subject 9 protection. At least you've got something in 10 there, and then you say it is not all 11 inclusive. You've got some other concerns 12 that -- and let it be up to the IRB to decide 13 what those are. 14 Would you accept that? 15 DR. FISHER: I guess my only 16 question would be how would someone know the 17 IRB didn't judge this correctly? 18 CHAIRMAN PRENTICE: By 19 documentation. 20 DR. FISHER: But I mean, what 21 would be the criteria? 22 CHAIRMAN PRENTICE: Like all of 71 1 the other criteria in IRB approval, you've got 2 to document what you do. Are you suggesting 3 that, as part of the IRB minutes, for example, 4 you would document this if it was a full board 5 meeting? 6 DR. FISHER: No. I was actually 7 thinking of threshold of substantive concerns. 8 CHAIRMAN PRENTICE: Thinking what 9 now? 10 DR. FISHER: Threshold. 11 CHAIRMAN PRENTICE: Well, it 12 depends upon how far you want to go in terms 13 of guidance. We are trying to give some -- at 14 least some guidance, but without being totally 15 prescriptive. I don't see how you can -- 16 Unless you want to provide an additional 17 narrative that describes further what we mean 18 by, for example, an impact on the risk/benefit 19 relationship. It depends upon how far you 20 want to go. 21 At least this gives some guidance 22 within the context of the recommendation. 72 1 DR. GYI: Celia, I wonder if we 2 might just remember that we are talking about 3 a lag time after the continuing review 4 information has already been submitted to the 5 IRB. So we are looking at how to give IRBs 6 some guidance in the event that the expiration 7 date has been triggered after the -- or during 8 the time that it was supposed to have been 9 reviewed or after the information had been 10 submitted. 11 So I can appreciate your comments 12 about how can we be assured of the fact that 13 the IRB hasn't done something roguish in its 14 nature, if you will, to say that they have 15 sort of overstepped their authority in looking 16 at this particular process. But I think that 17 we have to remember that this is somewhat of 18 a minor issue with regard to how we can 19 preserve the integrity of the approved status, 20 if you will, while there is that lag time that 21 has come about. 22 MR. NELSON: Yes. It is an 73 1 important point. We are not proposing a 2 change, at least with this recommendation, to 3 the continuing review process and how it is 4 conducted and all the other subjective 5 judgments that are being made at 100 different 6 levels throughout this entire process. 7 This is just when that process is 8 underway, we are not taking things to the 9 point they are today, which is to stop 10 everything, regardless of the level of 11 concerns or the level of loose ends that 12 remain from that review. 13 CHAIRMAN PRENTICE: Mike? 14 DR. GENEL: I wonder if this could 15 be rephrased in a more positive rather than 16 negative fashion to say something like, OHRP 17 should provide guidance on continuing review 18 to permit continuation of the research for 30 19 days within the expiration, etcetera, 20 etcetera; rather than having that at the end, 21 with the clarifications that Ernie has 22 suggested. 74 1 MR. NELSON: I think we can 2 rephrase that part, but what I was waiting for 3 was what you lumped under "etcetera, 4 etcetera," because it seems like we have to 5 come back to what would be the conditions 6 where OHRP would allow that, and we still have 7 to say it. 8 DR. GENEL: Well, very much the 9 language we have been talking about. I'm just 10 saying just turn that around and put the end 11 at the beginning. In other words, OHRP should 12 modify guidance on continuing review to permit 13 continuation of the research within 30 days of 14 the expiration date when the study has been 15 reviewed, etcetera. 16 DR. FISHER: Ernie, I am wondering 17 whether maybe Dan could type in your 18 suggestion, and let's see how it works. 19 MR. NELSON: I was afraid somebody 20 was going to suggest that. 21 DR. FISHER: Because it sounds 22 good. So let's see it concretely, and maybe 75 1 we can move ahead. 2 CHAIRMAN PRENTICE: Is that 3 possible, Dan? 4 MR. NELSON: I'll try. 5 CHAIRMAN PRENTICE: You want me to 6 read it again? 7 MR. NELSON: I think I've got it 8 here. Let me -- 9 CHAIRMAN PRENTICE: Jeff, while 10 Dan is typing, do you want to make a comment? 11 DR. BOTKIN: I guess my comment, 12 actually, was going to go a little bit in the 13 other direction. I am fairly happy with the 14 language as it is of giving IRBs a fair amount 15 of leeway here to determine these issues, as 16 they do in many other arenas. 17 In that regard, I guess I would 18 raise a question about other types of concerns 19 that may come up. Certainly, say, with the 20 collaborative oncology trials, we frequently 21 have difficulties with low accrual rates for 22 those studies, and question then whether the 76 1 studies ought to be continued, or there may be 2 evidence of inequitable recruitment of 3 subjects for whatever reason. 4 Now you know, are those human 5 subject protection issues or do they go to the 6 validity of the study more broadly? In that 7 sense, perhaps they are tangentially human 8 subjects, but they are perhaps not directly 9 human subject issues. 10 So I would be interested in your 11 response to that type of concern on continuing 12 review and how it fits with this 13 recommendation, again perhaps going to the 14 question of whether we ought to be saying 15 simply substantive concerns about the project, 16 anytime there's substantive concerns, 17 irrespective of whether it is directly related 18 to human subject protections. Perhaps that 19 ought to be the language we are thinking 20 about. 21 MR. NELSON: I took just a little 22 editorial license here, Ernie, but let's see 77 1 how this works: That there are no substantive 2 concerns in terms of the risk/benefit 3 relationship, informed consent, or other key 4 protections. 5 CHAIRMAN PRENTICE: Yes, I like 6 that. And, Jeff, I think that that would 7 accommodate your comments. If the accrual is 8 not sufficient, the study probably ought to be 9 halted. I mean, you can't -- That would 10 impact -- have a negative impact on the 11 risk/benefit relationship if you can't get the 12 data to complete the study. So I think that 13 would fall into "other key protections." 14 I think this provides -- It 15 provides more guidance than the original 16 version. We could expand this to, you know, 17 several pages. 18 That's not what we want to do, and 19 we want to provide what I would characterize 20 as key recommendations, and then when OHRP 21 gets these recommendations handed down from 22 the Secretary's office, it is their 78 1 responsibility to convert the recommendations 2 into guidance, and they certainly have the 3 prerogative to look at that and say, you know, 4 we need to expand upon this a little bit 5 further and provide additional clarification, 6 which is what we expect them to do. 7 I think there is a misconception 8 that whatever we pass here, if it is accepted 9 by the Secretary, it is given down to OHRP, 10 that's the absolute final version of it, and 11 they don't add anything to it. That is not 12 the case. 13 MR. NELSON: Thank you, Ernie, and 14 I think that is a key thing for us to remember 15 as we go through all these, because I'm sure 16 our words are not perfect on every line, but 17 the concept is what we are trying to get 18 across. 19 CHAIRMAN PRENTICE: So, therefore, 20 in the interest of moving on, if there is no 21 further pressing discussion, I would entertain 22 a motion on this particular recommendation. 79 1 James? 2 DR. POWELL: I move we accept this 3 recommendation as stated. 4 CHAIRMAN PRENTICE: Neil? 5 DR. POWE: Second. 6 CHAIRMAN PRENTICE: Second. 7 Further discussion? All those in favor, raise 8 your hands. Any opposed? Any abstentions? 9 The recommendation is approved. 10 MR. NELSON: All right. Well, 11 that's all for continuing review, and we will 12 now move on to expedited review, which is the 13 second major category that we formed working 14 groups to address early on. 15 Here, too, we were left with a few 16 tabled items from the last time around that 17 were endorsed in concept but needed some fine 18 tuning. Here, too, I will just spend a little 19 bit of time, but not as much in July in 20 recapping the underlining regulatory basis. 21 So regulations from both HHS and 22 FDA provide for an expedited review procedure, 80 1 as you know, under which the IRB chair or one 2 or more experienced members designated by the 3 chair may approve one of two broad sets of 4 actions: Research in categories appearing on 5 a list published in the Federal Register and 6 found by the reviewer to involve no more than 7 minimal risk -- so two components, two 8 criteria that must be satisfied there; or as 9 we just referenced, minor changes in 10 previously approved research during the period 11 of one year or less for which approval is 12 authorized. 13 I believe the list and the 14 regulation should be in your binder for 15 reference, if questions arise. 16 This is just a graphic I have used 17 to remind us that the level of review 18 generally tracks along and is dictated by the 19 level of perceived risk for any proposed 20 research, as we escalate from exempt to 21 expedited to full committee review, and then 22 crossing this somewhat blurry threshold of 81 1 minimal risk which we will talk about for the 2 last two hours today. 3 So expedited review should not be 4 confused with review light. As Felix just 5 said, the rigorous is expected to be the same 6 as with full review. Really, only the number 7 of reviewers performing or conducting that 8 review are different. 9 In reviewing the research, the 10 reviewers may exercise all of the authorities 11 of the IRB except that the reviewers may not 12 disapprove the research. Research activity 13 may be disapproved only after review in 14 accordance with the non-expedited procedures, 15 i.e., a full convened IRB meeting. 16 Expedited review is to be used 17 with minimal risk research, and is, therefore, 18 calibrated for that setting. As with review 19 by the convened IRB, expedited review must 20 fulfill all of the requirements for approval 21 found at 46.111 and Subparts B, C and D, if 22 applicable. 82 1 These are those eight criteria for 2 approval found under 46.111: That risk be 3 minimized; that there is an acceptable 4 risk/benefit ratio; that there be equitable 5 selection of subjects; that attention be given 6 to the informed consent process and the 7 documentation of consent with possible waivers 8 or alterations thereof, where appropriate; 9 that there is a monitoring plan for safety; 10 that privacy and confidentiality are 11 protected; and that, when appropriate, there 12 are additional safeguards for vulnerable 13 populations. And as Ernie referenced in the 14 previous recommendation, this is really what 15 we are trying to get at as substantive areas 16 of concern. 17 This is an abbreviation of that 18 1998 list of categories that are eligible for 19 expedited review at the time of initial review 20 for the study as a whole: Clinical studies 21 where an IND or IDE is not required; blood 22 samples by routine methods in small amounts in 83 1 healthy individuals; noninvasive prospective 2 collection of biological specimens; 3 noninvasive collection of clinical data; 4 materials that have been collected or will be 5 collected for non-research purposes; non-voice 6 video digital recordings for research; 7 individual or group behavior surveys, 8 interviews, oral histories. 9 These are two categories, eight 10 and nine: That address expedited review in 11 the setting of continuing review, so 12 continuing review of research previously 13 approved by the convened IRB with no further 14 direct subject participation; continuing 15 review of research not under an IND or IDE 16 where the IRB has determined and documented at 17 a convened meeting that the research involves 18 no greater than minimal risk and no additional 19 risks had been identified. 20 Those in the audience who apply 21 these daily or from OHRP will recognize we 22 have taken a little license with collapsing 84 1 some of these, but the full text and all the 2 nuances are again on that 1998 list. 3 Our working assumptions in the 4 area of expedited review are: That this is a 5 valuable mechanism to allow IRBs to triage 6 studies to an appropriate level of review, and 7 that expedited review affords effective 8 oversight of minimal risk research while 9 permitting the majority of IRB members to 10 focus their efforts on protecting subjects' 11 rights and welfare in research with 12 potentially serious or more serious risks. 13 To the extent that expedited 14 review can be used for minimal risk research, 15 the time and resources of IRBs can be 16 concentrated on protecting subjects that face 17 the greater levels of risk. 18 So these are our few specific 19 issues of concern in this area, again with a 20 reminder that several other recommendations in 21 this area have already been presented to and 22 approved by SACHRP. I think eleven in number, 85 1 if I remember the earlier head count. 2 This one remains, stemming from 3 the question that we raised and asked the 4 working group to consider: Does the 1998 list 5 of categories of research that may be reviewed 6 by the IRB through an expedited procedure need 7 updating or revision? 8 In particular, our discussion 9 focused on the social and behavioral sciences 10 where investigators and IRBs have 11 traditionally had difficulty fitting their 12 research into the current regulatory structure 13 and have indicated a need for greater 14 specificity in identifying research that may 15 be appropriate for expedited review. 16 Our subcommittee considered 17 several options for addressing this need, 18 including reordering of the '98 list, which we 19 concluded wasn't going to be beneficial if 20 people didn't want to keep reading down that 21 far. It wasn't a matter of just putting the 22 item we wanted to focus their attention as 86 1 number one. 2 It needed more help than that; 3 relabeling of the list to "help the social and 4 behavioral science folks find themselves in 5 that list and find their activities" or 6 revising the list to highlight and extended -- 7 and this is the approach we took: Highlight 8 and extend topical areas of social and 9 behavioral research and methodologies commonly 10 used in that research, since the perception 11 and the feedback we were getting as we polled 12 the community and from our own experiences 13 were that the elements were there, but we just 14 had to highlight them a bit more and direct 15 people's attention, if you will. 16 So this was our previous 17 recommendation that was presented but tabled 18 by SACHRP on July 31, and this was a proposal 19 to revise Category 7. Felix or Cathy or 20 Kelley, maybe while I'm talking you can help 21 orient members for which tab this would be 22 under, if they do want to pull up. Do you 87 1 have the book handy? 2 If somebody could, in the binder, 3 just let people know which section is the 4 Category 7. In case they want to look at the 5 current wording for reference, that might be 6 helpful. 7 Let me keep going here while that 8 is being done. So the existing Category 7, 9 again, in many of our minds is aimed to 10 encompass an allow for expedited review of 11 social and behavioral, other areas of 12 research. 13 Our proposed wording was that it 14 encompass research on individual or group 15 characteristics or behavior, including but not 16 limited to research on perception, cognition, 17 motivation, affective states, interpersonal 18 relationships, identity and language 19 communication, cultural beliefs or practices, 20 and social behavior. Again "including but not 21 limited to" is meant to say what it says, that 22 this is not an exclusive list, but are like 88 1 categories. Ernie? 2 CHAIRMAN PRENTICE: Page 3. 3 MR. NELSON: Page 3 of which tab? 4 CHAIRMAN PRENTICE: Tab H-3. 5 MR. NELSON: Tab H-3. Thank you. 6 So again, that will give you the current 7 wording of Category 7, if it helps to 8 reference that to see what we have done with 9 it. We are not completely rewriting as much 10 as breaking things apart just a little bit and 11 adding a bit, too. 12 "Or research employing methods 13 commonly used in social, behavioral, 14 epidemiologic health services and education 15 research" -- and some of those items there 16 were added at the suggestion -- the helpful 17 suggestions of our ex officio members -- 18 "including but not limited to survey, 19 interview, oral history, participant 20 observation, ethnographic focus group program 21 evaluation, human factors evaluation, or 22 quality assurance methods." And I see I've 89 1 forgotten a parentheses, but hopefully, you 2 can trust that I will insert that when we 3 relay it. 4 The note at the bottom is there in 5 the current wording, and we haven't done 6 anything with that, just noting that some 7 research in this category may actually be 8 exempt, and this listing refers only to 9 research that is considered not to be exempt. 10 With that, this is now open for 11 your recommendation. Celia? 12 DR. FISHER: I think this is very 13 good, and I think the SBER community will be 14 very happy. 15 I would suggest consideration of 16 an addition, perhaps not that it belongs here. 17 But the problem that SBER researchers have is 18 not with the procedures. It is not whether to 19 survey procedure ethnographic. The problem as 20 they perceive it is an overestimation of harm 21 that is encountered within those procedures. 22 So, for example, asking an 90 1 adolescent a question about sex; asking 2 somebody a question about if they are upset 3 about a catastrophic event. So it is really 4 the kind of nature of the content of those 5 procedures that are of greatest concern to the 6 SBER community. 7 One of the ways that we attempted 8 to address that in Subpart D that you -- you 9 know, obviously, that is just for children, 10 but that you might want to look at for Subpart 11 A was how it seems easy to talk about -- Well, 12 nothing is easy. But a routine examination in 13 terms of physical, if you are going to get a 14 blood draw or you are going to be asked to do 15 something to measure your eyes, but there was 16 much less in terms of -- because the way the 17 language is, it doesn't say what exactly is 18 routine in terms of this substantive content 19 in a medical or psychological examination. 20 So what Subpart D did for children 21 was describe what those were as exemplars. 22 For example, a physician, typically, as the 91 1 child gets older may ask about sex and drug 2 use. That is a typical type of question. 3 The psychological examination's 4 routine, if you want to refer to the routine, 5 typically include questions that may have to 6 do with depression. 7 So I think what is needed here is 8 to look at helping IRBs with what is a routine 9 examination and what are exemplars of daily 10 life for these social science equivalents, and 11 that, I think, would be extremely helpful. 12 MR. NELSON: All right. 13 CHAIRMAN PRENTICE: Celia, may I 14 suggest that what you are really talking about 15 is the next topic, and that is minimal risk 16 and how that is defined and applied in terms 17 of examples to the social/behavioral science 18 research areas that are listed on this slide. 19 MR. NELSON: Ernie has taken the 20 words right out of my mouth, because we have - 21 - As I noted on a couple of slides back, there 22 are two aspects to using this, and that is a 92 1 combination of being determined to be minimal 2 risk or no more than minimal risk, and being 3 on the list. 4 Right now, we are just dealing 5 with the list, and in this case -- This is 6 different than the previous recommendation, 7 because here we are actually taking something 8 published in the Federal Register and 9 proposing quite a specific expansion of the 10 wording. 11 The more conceptual framework that 12 you are talking about very rightfully is a 13 problem, and I think there is an 14 overestimation of risk. But we would argue, 15 I think, that the interpretation and 16 application of that definition is where that 17 belongs, and not in the specific regulatory 18 language on the list. 19 CHAIRMAN PRENTICE: Okay. So this 20 recommendation was tabled in July. it has 21 been brought back to SACHRP. Jeff? 22 DR. BOTKIN: I'd be interested -- 93 1 I like the flexibility here and expanding the 2 opportunities for including other 3 possibilities. Are there specific examples 4 that came to the table as part of your 5 discussion that would be included by adding 6 this language, and is there an opportunity to 7 be more explicit in the types of things that 8 you are thinking about as you are adding this 9 element of flexibility? 10 MR. NELSON: I must admit, in this 11 area -- and I'd have to look at the current 12 wording myself to see even what we expanded. 13 Our general sense was, frankly, that most 14 things people are doing can be already 15 accommodated in the existing language. But 16 for some reason, lack of understanding, 17 overestimation of risk, not enough examples, 18 that they were inappropriately excluding 19 certain activities, certain categories of 20 research, from expedited review. 21 That is what we have tried to, by 22 some of the inserts here, both by breaking out 94 1 to let them know that we can be talking about 2 either areas of research under A, or specific 3 methodologies employed in those research under 4 Subpart B here, or subsection B. 5 I guess the danger is, if what you 6 are asking is should we insert more examples 7 in this language, is that then -- We have 8 viewed the parenthetical listings here as 9 broad as we could stroke them right now 10 without listing every -- We are having trouble 11 finding examples that couldn't be lumped under 12 one of those areas of research that people 13 might want to be able to expedite. 14 I think the discussion we had last 15 time around was to add one or two sections, 16 which we did, to broaden it even further. But 17 maybe I would raise the question in the other 18 way: Are there things that should be included 19 that we have excluded by this list or that 20 wouldn't be captured by one of those broader 21 areas of research? 22 CHAIRMAN PRENTICE: Felix? 95 1 DR. GYI: When the subcommittee 2 met to discuss this, Jeff, we really did try 3 to look at some other specific categories and 4 areas of research, and what we found was the 5 more we added, the more it opened up for 6 debate as to whether we ought to add more or 7 what that meant. 8 So we tried to be somewhat general 9 in our approach with regard to being 10 inclusive. 11 The other thing that this group 12 might be interested in knowing is that, when 13 the original discussions took place regarding 14 this lumping of expedited review, and we heard 15 from folks like Charles McKay who said that, 16 when they were putting this together, the 17 expectation was that this list would be 18 reviewed on a yearly basis, and that there 19 would be some thoughtful deliberation as to 20 whether things ought to remain on this list, 21 come off the list, or added to the list. 22 So you know, I think that that is 96 1 the general premise by which we are 2 approaching this right now. Can we keep it 3 general enough so that it does capture the 4 essence of where the land mines exist 5 currently, especially with regard to non- 6 biomedical research? 7 So I would ask this committee to 8 think about it from that perspective to help 9 provide the guidance that we need for the IRB 10 and the research community. 11 One other thing, if I might add to 12 this. Some of this, I think, hinges on how we 13 are going to define research. So I wonder if 14 this is an appropriate time for us to even 15 discuss this or how we factor that into the 16 conversation and thinking of this particular 17 group. 18 CHAIRMAN PRENTICE: I take your 19 point, Felix, about how research is defined 20 could theoretically impact this, but the 21 recommendation 7 says research on individual 22 or group characteristics. So no matter what 97 1 OHRP does in terms of defining research, it 2 either is research or it is not research. 3 If it is research, and it is 4 research looking at individual or group 5 characteristics, then it would fall in 6 category 7. So I am not so sure you need to 7 delay consideration of this particular 8 recommendation until you see that guidance 9 from OHRP. 10 I would also make the comment that 11 what Felix said about Charles McKay's comments 12 concerning the expectation that the expedited 13 review categories would be looked at, if not 14 annually, certainly on a much more frequent 15 basis -- The last time they were revised, I 16 think, was -- what? -- '98? Ninety-eight. 17 That's quite a while ago. 18 I wonder if it would be in order 19 for us to consider a recommendation along the 20 lines of: OHRP should review these categories 21 at some interval, rather than leave it open- 22 ended, so we've got that down on paper as one 98 1 of our recommendations. 2 Did your subcommittee consider 3 such a recommendation? 4 MR. NELSON: We didn't, but 5 speaking for them, I think we would be happy 6 to endorse that. 7 CHAIRMAN PRENTICE: Okay. Let's 8 see if we could put this recommendation to 9 bed, and then we can talk about that next, if 10 it's all right with you. 11 Is there any further discussion 12 about Category 7? Hearing none, is there a 13 motion? 14 DR. POWE: I move that the 15 recommendation be accepted. 16 CHAIRMAN PRENTICE: Is there a 17 second? Nancy? 18 DR. JONES: Second. 19 CHAIRMAN PRENTICE: all right. It 20 has been moved and seconded. Further 21 discussion? All those in favor, raise your 22 hands. Any opposed? Any abstentions? 99 1 You are doing good work today, 2 people. We are going to be able to have -- We 3 had a long break. We are going to be able to 4 have at least a two-hour lunch if this 5 continues. Very good. 6 Felix and Dan, it is up to you as 7 to whether or not you want to talk about the 8 recommendation of re-review of the expedited 9 categories at a particular frequency, now, 10 later, what have you, or is this something you 11 feel like you have to bring it back to your 12 subcommittee? 13 MR. NELSON: I suspect this is not 14 going to be an area of much debate amongst our 15 subcommittee, and I'd be happy to let your 16 recommendation -- well, promote what you just 17 said to a recommendation for discussion right 18 now. 19 CHAIRMAN PRENTICE: All right. Is 20 that acceptable to everybody? Seems to fit. 21 Yes, Sam? 22 DR. TILDEN: Isn't that list also 100 1 adopted by the FDA? 2 CHAIRMAN PRENTICE: Yes. Correct. 3 DR. TILDEN: So the recommendation 4 wouldn't go just to OHRP, I wouldn't think. 5 CHAIRMAN PRENTICE: Correct. It 6 would involve -- 7 DR. TILDEN: It's sort of tongue 8 in cheek. I might suggest that we recommend 9 that the list be reviewed at least every 10 decade or more frequently. That's just a 11 tongue in cheek comment. 12 CHAIRMAN PRENTICE: Okay. Is 13 there -- McKay said every year. I'm not so 14 sure that every year is really practical, but 15 what would be a reasonable recommendation in 16 terms of frequency? 17 I mean, if this recommendation is 18 adopted by the Secretary and handed down to 19 OHRP and FDA, I mean, they are going to 20 actually have a formal process to look at this 21 at the interval specified. So what interval 22 is reasonable? Every three years? Five 101 1 years? What? Yes, what? You can't make 2 recommendations back there. You could 3 comment, but you can't make recommendations. 4 MR. NELSON: Roger, you can 5 whisper in my ear. 6 DR. ROMERO: I would recommend 7 every five years. 8 CHAIRMAN PRENTICE: You are 9 recommending every five years. All right. 10 You want to put that in the form of a motion? 11 DR. ROMERO: I make a motion that 12 we place before OHRP looking at expedited 13 review list every five years. 14 CHAIRMAN PRENTICE: Every five 15 years. All right. Is there a second for that 16 motion? 17 DR. BOTKIN: Second. 18 MR. NELSON: With harmonization by 19 FDA. 20 CHAIRMAN PRENTICE: With 21 harmonization by FDA. I assumed that is what 22 you meant. All right. So it has been 102 1 motioned and seconded. Now there is further 2 discussion. Mike? 3 DR. GENEL: What would that 4 involve? 5 CHAIRMAN PRENTICE: It would 6 involve OHRP staff looking at the expedited 7 review categories in consultation with the 8 various Federal agencies such as EPA and 9 Department of Education, etcetera. They would 10 all sit down, and they would look at it every 11 five years and say, hey, do we think that this 12 needs to be expanded, revised in some way -- 13 pretty much what we are doing right here, 14 looking at it. Is it working? 15 DR. GENEL: And presumably, if 16 they felt that it should be revised, it would 17 come back to SACHRP or somebody comparable to 18 SACHRP, if it existed. 19 CHAIRMAN PRENTICE: Not 20 necessarily. All right? It would depend upon 21 which committee wa working with OHRP and what 22 the charge of that committee was in 103 1 relationship to OHRP. OHRP can do things on 2 their own. They don't have to get permission 3 from SACHRP. So it wouldn't necessarily have 4 to come back to a SACHRP or a similar type 5 committee. Yes, Felix? 6 DR. GYI: I wonder if we might 7 want to get some comment from our ex officio 8 members and some of the other folks who have 9 to implement this, and get a sense of how we 10 might approach it. Five years may be too 11 long. It may not be long enough. Three years 12 may be not long enough. 13 CHAIRMAN PRENTICE: That's a good 14 idea. Any of the ex officio members want to 15 comment? Roger already likes the idea of five 16 years. Right, Roger? 17 MR. CORTESI: Right. 18 CHAIRMAN PRENTICE: Okay. Anybody 19 else? Where are we? 20 DR. SCHNEIDER: Hi. i do like the 21 idea of five years as well. I wonder right 22 now if I could ask a question. I actually 104 1 didn't know we were allowed to comment back 2 here, earlier on. 3 Is it possible to including 4 experimental methods. Behavioral scientists 5 routinely do experiments, say, in perception, 6 looking at different shapes, systematically 7 manipulated in experiments. It is actually 8 one of the most primary methodologies. 9 So I apologize for sort of moving 10 back to the earlier, but I think reviewing is 11 a very good idea, but one of the most 12 important ones isn't on the list right now. 13 CHAIRMAN PRENTICE: Well, this -- 14 First of all, this has already been -- 15 DR. SCHNEIDER: I know. I'm 16 sorry. I apologize. 17 CHAIRMAN PRENTICE: And I would 18 comment about experimental. The term -- I 19 know exactly what you are saying, but the term 20 experimental has a certain context that 21 becomes disturbing. 22 DR. SCHNEIDER: I know. I 105 1 understand that as well. 2 CHAIRMAN PRENTICE: All right. So 3 other ex officio members? Five years is on 4 the table at the moment. Anybody else? Jeff? 5 DR. BOTKIN: Does our language as 6 proposed preclude looking at it before five 7 years? Should we say at least five years, so 8 that should there be something that arises in 9 the meantime? 10 CHAIRMAN PRENTICE: Well, I take 11 your point. They could certainly do it 12 anytime they want, but that's probably an 13 appropriate clarification, at least five 14 years. 15 Since we are asking OHRP to do 16 this, Bern, would you like to comment on this? 17 DR. SCHWETZ: I like Jeff's 18 suggestion. What you are recommending is that 19 this be reviewed at least every five years. 20 So that if something in particular arises that 21 would make this a lot more useful and we are 22 just one year into that five years, it would 106 1 sure be good to look at it as we need to. But 2 not wait for more than five years to review 3 it. 4 It would be an interagency 5 activity. It would be a matter of revising 6 guidance, Mike. So it would be the same as if 7 we came up with some other guidance. We 8 wouldn't bring it to SACHRP to review it and 9 approve it. We would just do it. 10 Unfortunately, Sally Flanzer has 11 just stepped out of the room, and I think, if 12 some other agency had some specific comment 13 about this, it would have been Sally, but she 14 is not here. 15 MR. NELSON: I will note that 16 Sally was the source for some of the 17 additional elements that you see on the screen 18 in front of you right now. 19 CHAIRMAN PRENTICE: There is a 20 motion on the floor. Further discussion? 21 Hearing none, -- Yes? 22 DR. POWELL: