1 DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION MEETING MONDAY, APRIL 18, 2005 The Advisory Committee met in the Jefferson Ballroom in the Radisson Hotel, Old Town Alexandria, 901 North Fairfax Street, Alexandria, Virginia, at 8:30 a.m., Ernest Prentice, Ph.D., Chairman, presiding. PRESENT: ERNEST D. PRENTICE, Ph.D., Chairman BERNARD A. SCHWETZ, D.V.M., Ph.D., Executive Secretary CATHERINE SLATINSHEK, M.A., Executive Director THOMAS L. ADAMS, CAE, Member MARK BARNES, J.D., L.L.M, Member NANCY L. JONES, Ph.D., Member FELIX A. KHIN-MUANG-GYI, Pharm. D., Member SUSAN KORNETSKY, M.P.H., Member MARY LAKE POLAN, M.D., Ph.D., M.P.H., Member ADA SUE SELWITZ, M.A., Member SUSAN L. WEINER, Ph.D., Member EX OFFICIO MEMBERS: PEG BARRATT, Ph.D., National Science Foundation KATHRYN LYNN CATES, M.D., U.S. Department of Veterans Affairs ROGER CORTESI, U.S. Environmental Protection Agency SUZANNE GAYNOR, DrPH, RN, MBA, U.S. Department of Housing and Urban Development 2 DAVID LePAY, M.D., Ph.D., Food and Drug Administration VICTOR SCHNEIDER, M.D., National Aeronautics and Space Administration LAWRENCE UHTEG, U.S. Department of Commerce, NIST 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 LAURA ODWAZNY, Office of General Counsel 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 Welcome . . . . . . . . . . . . . . . . . . . . . .4 Report on Issues. . . . . . . . . . . . . . . . . .5 Summary of Charges of Various Subcommittees . . . . . . . . . . . . . . . . . . 11 Subpart D Subcommittee Report On Research Involving Children. . . . . . . . . . 15 Public Comment Session. . . . . . . . . . . . . .162 Subpart A Subcommittee Report Of Issues and Questions . . . . . . . . . . . . .196 Panel to Accept Subpart C Subcommittee Recommendations. . . . . . . . . . .221 Wrap-up Discussion. . . . . . . . . . . . . . . .240 4 1 P-R-O-C-E-E-D-I-N-G-S 2 (8:35 a.m.) 3 CHAIRMAN PRENTICE: Okay, folks, let us 4 get started. Good morning everybody. Good morning 5 SACHRP members, that is the official members of 6 SACHRP, OHRP representatives, and members of the 7 public. Thank you for attending our SACHRP meeting of 8 April, the second one this year. As usual, I go 9 through the SACRHP Charter, which was renewed in 10 September of 2004, and as you know, we are advising 11 the Secretary of HHS basically on all matters 12 pertaining to human subject protection. If you look 13 at our activities over the last two years, we have 14 accomplished quite a bit. These are the members of 15 SACHRP. And I would like to thank Cathy Slatinshek, 16 the Executive Director of SACHRP, and Kelley Booher 17 for keeping us on time, getting us here, and putting 18 all these books together for us. Cathy and Kelley, 19 you make our life easy. 20 Speaking of your books, your Briefing 21 Books, you have additional handouts that are marked 22 according to the tab that they should be inserted in, 5 1 so you might want to place them in your books. 2 Also, I once again want to remark about 3 the fact that SACHRP has a very functional working 4 relationship with OHRP. We work very closely with 5 OHRP and Dr. Bern Schwetz, and we have OHRP liaisons 6 assigned to all of the SACHRP Subcommittees, so I 7 thank you for all of your efforts. 8 I also want to comment on the involvement 9 of our Ex Officio members. I am sure that Bern will 10 talk about this a little bit more later, but they are 11 intimately involved in all of the activities of 12 SACHRP, providing us advice concerning what their 13 priorities and concerns are. 14 Next, I would like to invite Dr. Schwetz 15 to report on the Issues. Bern, I assume you are going 16 to do it from the table? 17 DR. SCHWETZ: Yes, Ernie, if I may. 18 Good morning to all of you and welcome. 19 I have a list of things, no one of which is tied to 20 the others, so it is just a series of pieces to talk 21 about. First of all, to confirm, the Department of 22 Homeland Security now is in the process of 6 1 implementing their Common Rule. They are trying to 2 decide how they are going to do that. But we, for the 3 first time, have -- and Mark is not here this morning, 4 but we have an Ex Officio representative from the 5 Department of Homeland Security, Mark Rosen, the 6 Deputy Associate General Counsel, Science and 7 Technology Directorate of DHS. So it is good to have 8 this new department onboard with implementation of 9 their Common Rule. They will be in the process of 10 setting up an IRB, or an IRB System. The research 11 that they have been doing and are in the process of 12 doing is being reviewed by other IRBs outside of 13 Homeland Security. So, it is good to see one more 14 department come in with the Common Rule. 15 In terms of regulatory actions, I do not 16 think there are any things new here to you, but just 17 to update you that the Equivalent Protections document 18 was published on March 24th, seeking public comment 19 over a period of 60 days. The full report is not 20 there, but the summary of the report of the working 21 group is there with a series of questions that we are 22 trying to seek information on. 7 1 The FDA Central IRB document for Multi-site 2 Studies was published on March 28th, again seeking 3 public comment for a 60-day period. David LePay is 4 not here at this point, but I am sure he will be, and 5 if any of you have questions about that, be sure to 6 talk to David. 7 The comment period for the IRB 8 Registration, the Joint FDA/OHRP Activity for 9 Mandatory IRB Registration, that comment period is 10 closed, and both FDA and OHRP are working to prepare 11 that final rule, which will come out later this year. 12 An update on the IOM activity to form a 13 committee to review the ethics of research and 14 prisoners, the name of this committee is almost as 15 long as some reports, but hopefully, there will be 16 some substance, in addition to the name. The IOM 17 Committee on Ethical Considerations for Revisions to 18 DHHS Regulations for Protection of Prisoners Involved 19 in Research. There must be a shorter version of that 20 that we will come up with this year. But they met for 21 the first time on March 16th and 17th. Nancy Dubler is 22 an expert adviser as liaison for the Board on Health 8 1 Sciences Policy. The Chair is Larry Dostin from 2 Georgetown University. I have a list of the members 3 if any of you want to know who else is on this 4 Committee. 5 I have been in the position of being at 6 the first meeting for several of these IOM Committees 7 in terms of the Government being a sponsor. I must 8 say this -- I was more impressed by this Committee 9 than any of the others that I have been at their 10 inaugural meeting, just in the sense of how well they 11 seemed to understand why they were there, and went 12 back and forth across the issues and the objective and 13 the charge and what they brought to the table, what 14 they were expected to do, so that I certainly felt, by 15 the end of that first day when I was there, that they 16 understood why they were meeting on this particular 17 issue, and also, what they were not there to do, which 18 is also extremely critical. They met for the second 19 day and continued to make progress. Julia Gorey is 20 our liaison to this Committee from OHRP and will be 21 involved with them on a basis as needed. So, we are 22 very pleased to have that group up and going. 9 1 In terms of plans for a Workshop on 2 Central IRBs, following-up on the Recommendations that 3 you made to us, we have had a series of meetings now, 4 laying out the plan for this internal -- not internal, 5 this Invitation-only Workshop, and we have now 6 modified the planning process a little bit to take in 7 some, -- or to work with some sponsors. So, we are 8 working with sponsors to further develop the plan for 9 this invitation-only workshop to review alternatives 10 to local IRBs, including Central IRBs, with the intent 11 that this workshop would be held probably after the 12 summer season, so I would hope that we would have it 13 in the September/October timeframe. And also that we 14 would have an open conference, not an invitation-only, 15 but an open conference, on this Issue after we have 16 had the invitation-only workshop, develop some 17 Recommendations that will come back to SACHRP, and 18 then have that be the basis for discussion at a larger 19 conference on alternatives to Local IRBs after that. 20 Several activities on Adverse Event 21 Reporting. The FDA has a Part 15 Hearing on March 22 21st where there were some 19 speakers who contributed 10 1 comments and information to the docket. The docket 2 has remained open until April 21st of this week, so 3 that -- we were very impressed by the comments that 4 came in on this Part 15 Hearing. For those of you who 5 have not attended one of these before, it is an 6 opportunity of the Government to listen, so that 7 people volunteered to come and present information, 8 present experience, present opinions, whatever they 9 had, on Central IRBs ¦ oh, I am sorry, on Adverse 10 Event Reporting -- and it was, at least, my feeling 11 that we heard some pretty diverse opinions about the 12 reporting process, about the role of IRBs, IRBs versus 13 Investigators versus Sponsors. So, there certainly 14 was a wide range of input. The next step is for the 15 FDA to review these comments and to develop their 16 plans for guidance and/or a rule. 17 OHRP is in the process of writing their 18 guidance. It has been written in a form that we have 19 under review internally, and with other agencies. The 20 Federal Adverse Event Task Force that you hard from, 21 Amy Patterson's Committee, continues to meet and make 22 progress toward their process of getting information 11 1 out sometime in the next few months. 2 The last thing that I would mention -- 3 you have heard me talk before about what we did last 4 fall in terms of interviewing members of the National 5 Commission and their support staff to help celebrate 6 the Belmont -- 25th Anniversary of the Belmont 7 Report. Well, we have now created this Belmont 8 Historical Archive that was -- parts of it were 9 tested last week and the transcript and the short 10 version of the video will go live today. So, if you 11 get onto our Web site, you will be able to get the 12 transcript, but you will also be able to see the short 13 version. The long version of the in-depth interviews 14 will become available, hopefully, soon after this. 15 But that is the next, and probably the last step of 16 this immediate 25th Anniversary Celebration. 17 Ernie, back to you. 18 CHAIRMAN PRENTICE: Thank you, Bern. 19 As is customary, we present a brief 20 overview of the charges of our Subcommittees. This, 21 of course, is the charge for the Subcommittee on 22 Research Involving Children, and suffice it to say, 12 1 they are looking at all aspects of Subpart D. As you 2 know, we have already had one letter of recommendation 3 accepted by the Secretary relative to the 407 Review 4 Process that has been implemented by OHRP. As a 5 matter of fact, SACHRP members, you have a status 6 report in your Briefing Books. The Subpart D 7 Committee continues to be very active under the Co- 8 chairmanship of Celia Fisher and Susan Kornetsky, and 9 I have to tell you, I have attended a number of the 10 meetings and I am so very impressed with the work that 11 they are doing. I think that they are making a very, 12 very significant contribution, and we are going to 13 hear from Susan -- Celia, unfortunately, cannot be 14 here -- but Susan will go ahead and present the latest 15 Recommendations of this Subcommittee. 16 We have a new Subcommittee, as you know, 17 Subpart A, under the Co-chair of Felix Gyi and Dan 18 Nelson, and like the Subpart D Task, they are looking 19 at all aspects of Subpart A in order to achieve the 20 goals of enhancing protection of human subjects and 21 reducing regulatory burdens that do not contribute to 22 the protection of human subjects. We are going to 13 1 hear a report from Dr. Gyi and Dan Nelson later on 2 today. 3 The Subpart C Subcommittee's work is 4 basically over. You have a Final Report of 5 Recommendations from the Subpart C Subcommittee in 6 your Briefing Books, and we would hope to bring that 7 to closure tomorrow, and then send a letter to the 8 Secretary. I would really like to compliment Mark 9 Barnes and Nancy Dubler, and all of the Subcommittee 10 members, for their fine work. 11 Our next task is to approve the Minutes 12 from the January 31/February 1, 2005 meeting. I am 13 prepared to entertain a Motion. 14 MR. BARNES: So moved. 15 CHAIRMAN PRENTICE: Second? 16 MR. ADAMS: Second. 17 CHAIRMAN PRENTICE: All those in favor? 18 (AYES.) 19 CHAIRMAN PRENTICE: Any opposed? 20 (NO RESPONSE.) 21 CHAIRMAN PRENTICE: Any abstentions? 22 (NO RESPONSE.) 14 1 CHAIRMAN PRENTICE: The Minutes are 2 approved by unanimous vote. 3 Now, for the overview of the meeting 4 Agenda today. We have got an ambitious Agenda, as we 5 always do. We have already had the Opening Remarks. 6 Bern has reported on the Issues. I have, once again, 7 summarized the Charges for the various Subcommittees. 8 At 9:00 o'clock, we are going to have the Report of 9 the Subcommittee on Research Involving Children and, 10 again, Susan Kornetsky will present that report. We 11 will take a break between 10:30 am and 10:45 a.m., and 12 then we are going to continue with that report. Then 13 we will break for lunch. 14 Now, I think it is important to note that 15 as Susan presents her report, we want this report to, 16 hopefully, culminate in Recommendations that we can 17 then send to the Secretary. We look at the task of 18 this particular Subcommittee in terms of components. 19 We have already had one component, that is, the 407 20 Recommendations. We think we are ready to present 21 further Recommendations with regard to 404, 405 and 22 406. So, bear that in mind as we proceed through that 15 1 particular aspect of the meeting. 2 Between 1:00 p.m. and 1:30 p.m., we will 3 have a Public Comment Session, and then between 1:30 4 p.m. and 3:00 p.m., we will have the Report of the 5 Subpart A Subcommittee, and it is going to be a report 6 of Issues and Questions that the Subcommittee is 7 beginning to address. It is not going to be a report 8 of any Recommendations because they do not, at this 9 particular point in time, have specific 10 Recommendations. 11 We will take a break between 3:00 p.m. and 12 3:15 p.m. and then we are going to continue between 13 3:15 p.m. and 4:15 p.m. with the Report of the Subpart 14 A Subcommittee. 15 Then, 4:15 p.m. to 4:30 p.m., we will have 16 the Recommendations to accept Subpart C. That is the 17 report that Mark Barnes and Nancy Dubler developed, 18 and you all have that in your Briefing Books. 19 From 4:30 p.m. to 5:00 p.m., we will have 20 a wrap-up discussion of Committee business, and then 21 we are going to adjourn at 5:00 p.m.. 22 Are there any questions about the day's 16 1 Agenda? 2 (NO RESPONSE.) 3 CHAIRMAN PRENTICE: All right. Susan, you 4 are going to get an extra seven minutes. 5 MS. KORNETSKY: Good morning. Can 6 everyone hear me okay? I am not Celia Fisher. As 7 most of you know, Celia has done all the other 8 presentations. I am going to be doing today's. She 9 apologizes for not being here, but we spoke before 10 this. 11 A couple of comments that I want to sort 12 of make, and Ernie alluded to this. What we tried to 13 do -- we have had one other Subcommittee Meeting -- 14 what we tried to do was to take the list of concerns 15 that Subcommittee -- that SACHRP had and really work 16 with them and integrate them into some type of final 17 report. And I have to say that -- Ernie alluded to 18 the fact that we are hoping today, at the end of 19 today, to have recommendations for a final report. 20 Both Celia and I feel confident that the Subcommittee 21 really -- we have been at this for over a year, and 22 have turned things upside down, inside out, and 17 1 really, I think, they have done as much as they can 2 with it. So, it is certainly up to you now to listen 3 to what they have done and to make recommendations and 4 to work with it. But I do not think that there is 5 much that we can take back to the Subcommittee for re- 6 examination. But, obviously, you folks need to 7 massage it and do whatever you want to do with it. 8 The other thing I just want to mention is 9 that I had the opportunity last Thursday to present to 10 -- in New York at Columbia University, to talk about - 11 - they wanted me to do a presentation on Pediatrics, 12 and I took it as an opportunity, at least the stuff 13 that we have publicly discussed here, to put out on 14 the table some of the concepts. This was 17 different 15 institutions, all that have some type of Pediatric 16 review. And I really wanted their input, whether they 17 thought it was helpful, whether it was clear, and I 18 have to say -- and I do not want to brag about this or 19 seem bias, but it was very, very well received. I 20 mean, they really felt that these were things that 21 they could work with, ways of looking at things that 22 they had not, and the feedback was positive. So, just 18 1 from the standpoint of the IRB world, I think we are 2 going in the right direction, and that was very 3 positive to hear. 4 So, today, the aim is -- what we are going 5 to do is we are going to go through the three 6 different categories, 404, where we have made some -- 7 we have conditionally accepted those things, but I 8 think, wisely, you as a Committee, have asked that we 9 have the opportunity to go back because, as you know, 10 the Pediatric Regulations build on each other. So, I 11 am going to go over that. Then we will pause for 12 questions. We will then go into 406, which is greater 13 than minimal risk with no potential for direct 14 benefit. We had some extensive discussions and there 15 were some very good points that you folks brought out 16 at the last meeting, and we will talk about that. 17 Then we will go into 405, which was introduced, -- we 18 didn't have quite as much time to talk about it. I 19 think we might find it less controversial, but we will 20 have lots of discussion about that. So, that is what 21 I am going to do this morning. 22 MR. BARNES: Can I ask you a question? 19 1 MR. KENNEALLY: Yes, Mark, please. 2 MR. BARNES: Is this, like, meant to be 3 the final report of the Subcommittee or is this the 4 final report on the definitions, and you are going to 5 continue work on other issues? 6 MR. KENNEALLY: That is up to Ernie and 7 Dr. Schwetz. My understanding is that, if we can 8 finalize this, there are probably on there some 9 suggestions at the end of other directions that we 10 will go to. I mean, it is really up to them, and I 11 will let Ernie comment whether he wants us to continue 12 to work. My sense is that they do; that is what I 13 have heard. But, really, anything that we do, this is 14 the basis. This is really -- we have not looked at 15 issues of consent, assent, -- there was some interest 16 in how we apply this to placebo trials and other 17 things. So, this really has to be the floor, and we 18 will leave it up to them. But this is, hopefully, the 19 wrap-up of this and the definitions. 20 So, this is our Subcommittee. I have to 21 say I have been continually impressed with these 22 individuals and the thought that they have given to 20 1 the Issues. And really, there are things that we have 2 gone 360 degrees on, where we recommended one thing 3 and then came out totally different. So, I think they 4 really have challenged the issues and themselves as 5 experts to think about these things. 6 So, the meeting goals today are really the 7 406 and 405, and to really sort of thrash through 8 those and see what the Recommendations are. 9 So, just to review again, for 404, which 10 is research that involves minimal risk, regardless of 11 whether there is a potential for direct benefit. 12 These were the Recommendations that were conditionally 13 approved by SACHRP. This is really just the quotation 14 from the Regulation of 404, that, "IRBs can approve 15 research that involves no greater than minimal risk, 16 with or without potential direct benefit, as long as 17 there are provisions made for soliciting the 18 permission of the parents and assent of the child." 19 So, the first thing that we ¦ what we 20 conditionally agreed upon was that we were going to 21 apply an absolute definition to "minimal risk" and we 22 used the wording that, that absolute definition would 21 1 be encountered by "normal, average, healthy children 2 living in safe environments, in daily life or during 3 the performance of routine physical or psychological 4 examination or tests." And to remind you, this is 5 very consistent with NHRPAC and the IOM Reports and we 6 really have not strayed too far from that definition. 7 Proposal 2 really recognizes the fact that 8 the minimal risks should be age indexed. As we are 9 all aware, there is a lot of difference between the 10 way a 2-year-old and a 17-year-old look at different 11 things in their lives and their parents do. So what 12 this is basically saying is that "It should be indexed 13 to the risk in the daily life and routine medical, 14 physical exams experienced by children the same age of 15 the subject population." 16 The third proposal really recognizes the 17 upper limits of risk and harm and that the uniform age 18 index definition of minimal risk should not represent 19 the -- should represent the upper, not lower, limits 20 of risk to which children can be exposed. 21 The fourth is really that research 22 procedures involving children can be approved as 22 1 minimal risk if the "probability" and "magnitude" -- 2 those are words that are used right out of the 3 Regulations -- of harm are equivalent to risks of 4 daily life or routine examinations with respect to 5 three different areas: duration, cumulative 6 characteristics, and reversibility of harm. So, what 7 this is saying is that when we are talking about 8 normal child types of care and visits, that the 9 procedures do not necessarily have to be the exact 10 that are done at those times, but really have to be 11 equivalent to the types of things that are done, and 12 the three areas that you would think about it is the 13 duration, the characteristics, and the reversibility 14 of harm. Again, this is very consistent with the IOM 15 and NHRPAC Reports. 16 The fifth, really, sort of recognizes that 17 the potential, when we are thinking about the daily 18 life of children, the well-child visit, that this 19 could be a good reference. What we are saying here is 20 that routine medical examinations really have no 21 precise universe so that they accept a definition, but 22 what we opted called the "Well-Child Care Visit" is 23 1 one reasonable basis for comparison to routine medical 2 and psychological examination or test. So, this is 3 again, some way of trying to ground what we mean by 4 "daily lives of children." 5 This was taken from the IOM. Again, these 6 are some examples. I do not think that this should be 7 interpreted as definitive, but some examples of the 8 types of things that go on during well-child care 9 procedures, again, to help people think about, "Does 10 it seem equivalent, in those three characteristics, to 11 these procedures?" 12 Psychological was a little bit harder to 13 think about because, as the Committee thought about 14 this, once someone is being asked to undergo sort of 15 psychological or behavioral types of assessments, 16 there is usually some type of issue. So, is there any 17 type of "routine" psychological evaluation that 18 children have. So we -- we played with this for a 19 while and really felt that this, again, represents the 20 types of procedures under psychological and behavioral 21 types of research that would -- could be considered 22 minimal risk. We have the list up here. You have 24 1 seen this list before. That is Proposal 6. 2 Proposal 7 really is the statement that, 3 regardless of where the research is being conducted, 4 that we need to use the same type of uniform standards 5 in international research; that we are not going to 6 change the standard because children have different 7 risk environments or whatever in different parts of 8 the world, so that we need to have the standard. And 9 we have some examples of how it does play out a little 10 bit differently internationally, but that basically we 11 are not going to change the standard. 12 So, this is a summary, again, of how we 13 are thinking about interpreting "minimal risks" that 14 goes over what we just discussed and I just want to 15 pause here to see if there are any questions or 16 concerns about this. Again, this is the basis, so 17 this is important. This is probably about the third 18 time, so we want to really sort of hear what people's 19 issues or concerns are. 20 DR. WEINER: A comment. 21 MS. KORNETSKY: Susan? 22 DR. WEINER: On Proposal 2, my only 25 1 comment is that we say that it should be "age 2 indexed." I guess I would add "age and developmental 3 status." So long as the subject is a minor, the 4 developmental status matters as well. 5 MS. KORNETSKY: I think that is certainly 6 a clarification that is in line with what we are 7 thinking, absolutely. 8 Mark? 9 MR. BARNES: On 4, can you just go back to 10 the way you stated "4" in the slides, please? 11 MS. KORNETSKY: Yes. 12 MR. BARNES: What you really ¦ I mean, 13 what is implied in that is not only those risks that 14 are equivalent to the risks of daily life, but those 15 that may be less than the risk of daily life? 16 MS.KORNETSKY: Yes. 17 MR. BARNES: So you might want to actually 18 just say "equivalent to" or "less than." 19 MS. KORNETSKY: "Equivalent to or less 20 than." Easy enough. 21 Tom? 22 MR. ADAMS: Just a question, going back to 26 1 the first one, use of the term "safe environment." 2 Did the Committee look at doing any type of additional 3 guidance similar to what you did with the well child 4 as to what "safe environment" means, particularly as 5 it would relate to the last recommendation -- the last 6 proposal which would require it to be similar to 7 standards in the United States? We have done 8 international. 9 MS. KORNETSKY: We did not specifically 10 talk about what ¦ you know, to further define what a 11 "safe environment" means. I think, obviously, this 12 was put in there because we really -- there is a lot 13 of environmental type of research that goes on with 14 kids, and we want to be sure to address that. The 15 reason really for putting it in, and we can -- I can 16 bring that comment back to Celia -- was that we did 17 not -- we were very concerned that we did not feel 18 that if you had a research protocol of children who 19 lived in violence-prone neighborhoods or in areas in 20 Africa with lions walking through the village, that 21 that would be interpreted that they have greater risk 22 in their daily life, therefore, it was -- you know, we 27 1 wanted rated. But actually, I do not think we did -- 2 Ernie, I do not -- I am going to rely on Ernie for 3 some of the discussion, too, because he has been at 4 most of the -- whether we actually thought about, sort 5 of, a further definition of what we mean by "safe." 6 CHAIRMAN PRENTICE: I do not recall any 7 further efforts to clarify what that means. 8 Obviously, there are relative degrees of safeness, 9 depending upon the environment. Certainly, in some 10 countries, what is safe there would not be the 11 equivalent of what is considered safe here. That is 12 kind of hard to get a handle on. 13 MS. KORNETSKY: Is there a recommendation 14 of a way that you would like to expand on that? I 15 mean, this is your report now, folks. That's the 16 message. So, if there are recommendations that you 17 want to make, to add to this, to clarify it, we 18 certainly -- that is why it is here. 19 MR ADAMS: It is interesting, the 20 standpoint that I think everybody has an idea of what 21 a "safe environment" would be. But it is difficult to 22 -- it is difficult for me to see how cross-culturally 28 1 you are going to be able to arrive at the same 2 definition as to what is safe. I am not saying we 3 should take it out; I am just trying to ¦ 4 MS. KORNETSKY: I think what we are saying 5 is that what we are using as a -- I am not so sure 6 that we need to have cross-cultural definitions of 7 "safety." I think what we are saying here is that 8 what we would apply as a "safe environment" in the 9 United States would be the same type of criteria we 10 would use. I mean, that is the point of saying that 11 we are going to have one standard. So, I am not so 12 sure that we would want to get involved in saying, 13 "This is what is safe here." The bottom line is these 14 are the standards that we are developing here in the 15 United States and that we have got to think of those 16 standards. Just because children cross-culturally may 17 not live in a safe environment does not mean that we 18 should be subjecting them to greater risk. I 19 understand, you know, you are sort of concerned on how 20 to expand that, but I think the bottom line will be -- 21 and that is why our last recommendation is that this 22 has to be applied. 29 1 CHAIRMAN PRENTICE: Susan? 2 MS. KORNETSKY: Yes. 3 CHAIRMAN PRENTICE: As long as we have the 4 uniform standard definition out there, I wonder 5 whether it might be clearer if we were to revise that 6 slightly by transposing some terms, and I am 7 suggesting that the definition of "minimal risk" at 45 8 CFR 46, when applied to Subpart D should be 9 interpreted as those risks "encountered during daily 10 life," by normal, average, healthy children living in 11 safe environments, or during the performance. In 12 other words, take the "daily life" and put it right 13 after "encountered" because the way it reads now is 14 a little bit disconnected. "Safe environments in 15 daily life." Do you follow me? 16 MS. KORNETSKY: Yes. 17 CHAIRMAN PRENTICE: Would you agree to 18 that? 19 MS. KORNETSKY: Yes, I think that is fine. 20 CHAIRMAN PRENTICE: Okay. Also, your 21 examples of well-child procedures, after Proposal 5, 22 do you see that? 30 1 MS. KORNETSKY: Yes, I do. 2 CHAIRMAN PRENTICE: Okay. I was not 3 clear about what was meant by the term "guidance and 4 education for the child, the parents or both" in the 5 context of a research procedure. 6 MS. KORNETSKY: I am trying to think -- 7 because I was on the IOM Committee -- what was meant 8 by that. I think what happens -- a lot of times what 9 happens at well-child care, is there is a lot, -- in 10 addition to the actual physical exams and whatever, 11 that there are education types of things that are done 12 -- how to use seat belts, issues about -- perhaps 13 guidance about, you know, smoking, avoiding certain 14 types of, you know, sexual practices and those types 15 of things. So, I think that is what it is getting at, 16 sort of, the counseling that goes on between the 17 provider and either the family or the child or 18 adolescent. 19 CHAIRMAN PRENTICE: Which would be part of 20 a research intervention, like a smoking cessation-type 21 intervention, is that where you are going? 22 MS. KORNETSKY: It could be. I mean, 31 1 those types of interventions certainly -- there are a 2 lot of educational types of interventions on how to 3 keep kids, you know, safe and off drugs and those 4 types of things. So, I am pretty sure that that is 5 what it is referring to. 6 CHAIRMAN PRENTICE: You might want to 7 think about a greater clarity in terms of that. 8 MS. KORNETSKY: Okay. 9 CHAIRMAN PRENTICE: I understand what you 10 are saying. Perhaps "guidance and education 11 interventions." Something along those lines? 12 MS. KORNETSKY: Okay. 13 CHAIRMAN PRENTICE: You might talk to 14 Celia about that. 15 MS. KORNETSKY: That is fine. That is 16 fine. But that is what we are trying to get at. 17 CHAIRMAN PRENTICE: Okay. Proposal Number 18 6. 19 MS. KORNETSKY: Yes? 20 CHAIRMAN PRENTICE: Can you just flip the 21 slides? 22 MS. KORNETSKY: (Changing slides.) 32 1 CHAIRMAN PRENTICE: There you go. The 2 first four make sense to me. Tests, scales, tests, 3 tests. 4 MS. KORNETSKY: Okay. 5 CHAIRMAN PRENTICE: And then the fifth says 6 "neurological and motor disorders." Is that 7 screening? 8 MS. KORNETSKY: Yes, it would -- I would 9 assume that it would be screening. 10 CHAIRMAN PRENTICE: Okay, I would suggest 11 adding that then. "Social development assessment." 12 MS. KORNETSKY: Yes. 13 CHAIRMAN PRENTICE: Okay, "Family and 14 peer relationship assessment" or "relationships 15 assessment?" 16 MS. KORNETSKY: Yes. 17 CHAIRMAN PRENTICE: Would you agree? 18 MS. KORNETSKY: Yes. 19 CHAIRMAN PRENTICE: Okay. And I do not 20 know what "emotional regulation" means. 21 (LAUGHTER.) 22 CHAIRMAN PRENTICE: I certainly think I 33 1 need some of that, but I am not quite sure what it 2 means. 3 MS. KORNETSKY: Celia would be the expert 4 on this, but I think what is means is there are 5 certain types of scales, you know, that are used with 6 kids and adolescents that sort of -- you try and get 7 a handle on how they are feeling emotionally. You do 8 this probably in the quality of life type assessments. 9 CHAIRMAN PRENTICE: Then may I suggest 10 "emotional regulation scales?" 11 MS. KORNETSKY: That is fine. And the 12 other one would also have to probably be "scales." 13 CHAIRMAN PRENTICE: Yes. 14 MS. KORNETSKY: The feeling of sadness and 15 all this on scales. 16 Now, you know, when we write the report, 17 I think it is really important to have there remain 18 flexibility. So, this should not be interpreted -- 19 and we will be very careful -- as you know, this is 20 it, everything here, because it is possible that any 21 one of these in a specific population or different 22 things, you know, could be greater than minimal risk. 34 1 So I think these are going to be presented as 2 examples, you know, these are the types of things that 3 we need to be thinking about. 4 CHAIRMAN PRENTICE: Would you move to 5 Proposal 7. 6 MS. KORNETSKY: Yes. 7 CHAIRMAN PRENTICE: Just so everybody 8 knows, this is a different recommendation than you 9 have in your books. It was revised this morning, and 10 what it is saying here is that you cannot have one 11 standard of minimal risk in this country and a 12 different standard in other countries. That addresses 13 your point, Tom. It would be almost impossible to 14 come up with a culturally specific, country-specific 15 relevant definition of "minimum risk" tied to daily 16 life. So, this is the best we can do and we think it 17 is very, very important that we maintain, you know, 18 the same standards that we have here when research is 19 conducted in other countries, as much as is feasible. 20 And if you look at the definition of "minimal risk," 21 that is the floor; that is the threshold level. If 22 you do not meet that definition, you still have an 35 1 opportunity to have research protocols improved under 2 405 and 406. So, I would think that you might have a 3 situation internationally where a protocol perhaps 4 would be approved under 404 here, but it might not be 5 approved under 404 there. It might be approved under 6 406, for example. So I think there is some 7 flexibility built in to this recommendation that would 8 accommodate some of your concerns. 9 MS. KORNETSKY: Yes. We felt very 10 strongly to make a statement like this because there 11 is so much international research and we think that 12 that is important. 13 Ada Sue? 14 MS. SELWITZ: I want to ask one question. 15 It really is Proposal 7 I am having a hard time, sort 16 of, getting a grasp on. In developing Proposal 7, did 17 you get input at any point from individuals that work 18 in the international community and their reaction to 19 this particular proposal? 20 MS. KORNETSKY: Well, the only thing I -- 21 I mean, there are members of the Committee who have 22 given careful thought to this. Skip Nelson, who has 36 1 done a lot of work in and lectured and stuff, you 2 know, internationally, was on the Committee. Were 3 there people who specifically, 4 -- researchers who do international research 5 represented? No, there were not. But, what would be 6 the concern, Ada Sue, that this would prohibit certain 7 types of research? I mean, you have to remember, this 8 is research that falls under Health and Human Service 9 Regulations, which are our regulations here in the 10 United States. There is a lot of discussion 11 internationally about the standards that we use, and 12 we felt it was very important to say they had to be 13 the same. It is a tricky area, but I do not know how 14 to -- Felix? 15 DR. GYI: I have a similar concern as 16 well. It is not so much from the perspective of 17 having principles that we can apply, but rather having 18 the impression of imposing a level of cultural, as 19 well as regulatory imperialism to say that this is the 20 standard that we want to apply across-the-board. I 21 think we are all trying to -- we are all wrestling 22 with the same issue, which is, how do we allow for 37 1 application of these principles that have so much both 2 real life application as well as emotional overtones 3 to it. So, at least in some of the experiences that 4 I have had, when we talked to researchers and IRBs 5 trying to apply some of these, that they do not know 6 how to wrestle with this. They do not know how to 7 apply assessment of risk in different settings. So, 8 when we say things like "the uniform standard must 9 apply internationally," on the surface it almost 10 sounds as if what we are doing has to apply over 11 there. I wonder if we are wrestling with those types 12 of issues here -- that there is an application, by the 13 way, to the Subpart A Subcommittee as well, because 14 the definition of "minimal risk" has been deferred for 15 the larger Committee discussion, so that we do not 16 conflict with what the Subpart D Group is doing. And 17 I see that that will need to be coordinated and 18 considered in some ways. I wonder if you have any 19 suggestions or thoughts along these lines? 20 MS. KORNETSKY: No, we are all wrestling 21 with this. I mean, you know, the option is to say 22 nothing or to try and expand what we mean by this. I 38 1 think expanding what we mean by this -- and I 2 recognize your point, too. It is a tough area to try 3 and figure out what to say or not say anything at all. 4 Susan, and then Mark. 5 DR. WEINER: It seems to me that, you 6 know, we have to remember that we are talking about 7 parents signing permission for their kids to 8 participate in research. So, to some extent, we are 9 talking about the proxy for the parents' role. And I 10 think that if anywhere there is a "community 11 standard," that is where it is. So, the question 12 really is, in this community for the people judging 13 the ethics of a particular trial internationally, in 14 this community, is this an acceptable level of risk 15 for these families. The only people who can really 16 judge that is not us, but those participants in the 17 community. So, it is possible then to look at the 18 question of uniform standard as an internal standard, 19 as an internal cultural standard, it is a standard of 20 mothers, rather than thinking that the burden of 21 definition has to be on the external environment. 22 MS. KORNETSKY: I think I could say that, 39 1 Susan, and maybe you were not going to -- my concern 2 would be in some cultural communities. You know, when 3 someone comes to you and asks you to participate or to 4 do something, you do not question it and you do it. 5 So, if someone came to a community with children, 6 asking their parents to participate, you know, 7 culturally you have this issue, you try informed 8 consent or whatever, but the parents -- you know, you 9 do not question, sort of an authority-type of figure. 10 So, by saying the parent ultimately protects, that is 11 sort of problematic. I do think we do need a level 12 for IRBs so that something -- that parents are not 13 asked for things that perhaps they would say "yes" to 14 because of the culture of respect in the medical 15 community or whatever type of community. 16 DR. WEINER: I understand that kind of 17 argument and it is perfect because you can apply it 18 also to situations in which -- you can apply it to 19 the correlative study situation in which kids are 20 protocols. That is my theory anyway. 21 MS. KORNETSKY: Mark? 22 MR. BARNES: You know, I have had some 40 1 experience -- in fact, over the weekend, two days ago, 2 in training IRB members in Africa and there is -- I 3 think this is probably the right thing to do, the way 4 that you have, -- the conclusion that you have arrived 5 at, but I just wanted to make two reflections on it. 6 One is that really what this -- if you look back and 7 you think, kind of at the 20,000 foot level, about 8 what we are really all doing when we try to apply the 9 Common Rule, is we are trying to say, "these are the 10 standards that should apply when our U.S. Government 11 funds research." I mean, that is really at base of 12 what this is about, and it is about a public policy 13 interest in having good and ethical research that will 14 be funded by Federal dollars. Because all the FWA 15 jurisdiction flows from the receipt of Federal money, 16 and when you talk about Subpart D, then there are many 17 IRBs that would only apply Subpart D or Subpart C to 18 directly Federally funded research projects. So, in 19 that sense, -- adopting this regulation or this 20 interpretation of the regulation, I should say, is 21 really -- I mean, what it is really saying is that 22 when U.S. Government money is used to fund research, 41 1 then the level of risk that should be -- that an IRB 2 should use to analyze the research should be no 3 different for a child in Tanzania than for a child in 4 Wichita, Kansas. That is really -- and so it is 5 saying that we are not going to allow children to be 6 subjected to a higher level of risk than we would 7 allow American children to be subjected to, which is - 8 - sounds appropriate, and I think it is probably the 9 right thing to do because the thought of the alternate 10 is, sort of, an odious thought, especially when you 11 are talking about public money. So, that's one point. 12 The other point, though, is that it is 13 odd, and if you think about the consequences of it, 14 because if you talk about international research, then 15 the way that it is actually done, you know, in most 16 places, I mean when there is Federal money involved, 17 is that the domestic IRB, the U.S. IRB is applying the 18 standards and considering the proposal, and at the 19 same time, there is a parallel process going on in- 20 country with an IRB composed, for example, of people 21 from Mumbia Medical College in Tanzania, which acts as 22 an IRB for many research projects in Tanzania. So, it 42 1 is somewhat odd to think that the people in Tanzania, 2 since they have signed an FWA as well, are going to 3 have to be -- when they consider an application, they 4 are going to have to be applying an American standard 5 and how are they going to know, sort of, what the 6 American standard is. I do not think that they would 7 be any better positioned to know that bit of cultural 8 relevance than the Mass General or your IRB or the 9 Harvard IRB could understand, you know, the cultural 10 context and what would be a safe environment for an 11 average child in Tanzania. So, there is -- so, 12 adopting this does have problems in implementation 13 like that, but I go back to my first point -- I think 14 the alternative of the first point is probably not a 15 good alternative. So, it is probably better to live 16 with the higher standard and just understand that it 17 means that even if the Tanzanian IRB would end up 18 applying a lower standard, at least the American IRB 19 is going to have this and would apply the same 20 standard and so we would end up with a higher 21 standard. 22 MS. KORNETSKY: You know, it is 43 1 interesting because just this past week, Helen McGough 2 gave a presentation on International Research and we 3 think of "International" sort of, you know, off the 4 shores of the United States, but it is not. There are 5 cultures here within the United States that the same 6 issues arise. So, we are making the statement here 7 for international, but you do not have to go across 8 the ocean to have some of these exact same issues with 9 cultures and perceptions and safe environments. You 10 find it right here in the United States. So it is 11 tricky. 12 Ernie? Okay, any other questions on 404? 13 CHAIRMAN PRENTICE: By the way, the way 14 we are going to work this, with your approval, is 15 rather than vote on the proposals as Susan gets done 16 talking about them, we are going to wait until the end 17 and then we are going to go through each of the 18 proposals and, hopefully, reach a vote on those. 19 Would that be acceptable? All right, Susan. 20 MS. KORNETSKY: Okay, great. So, this is 21 where it begins to really get interesting. I just 22 want to remind the Committee members that last time, 44 1 it was amazing because I sort of sat here as you 2 presented and watched everyone's faces and said, "Oh, 3 my gosh, I am overwhelmed; everyone else must be 4 overwhelmed." So, in really going through this, we 5 really tried to simplify it and I think the concern 6 really that was brought up is this was so overwhelming 7 and then, sort of, translating that into "Does this 8 mean that IRBs are going to have to document every one 9 of these ten things?" You know, this is regulatory -- 10 it could be "regulatory burden," it is getting out of 11 hand. So, we really kept that in mind and I really 12 pushed that at the Subcommittee meeting to simplify 13 things. Hopefully, we did that. But you will 14 certainly let us know. 15 The other comment that really came up here 16 was that concrete examples would help, that this was 17 all sort of conceptual in thought. You know, give us 18 some examples to sort of think this through and 19 whether it really works. So, we have tried very hard 20 to do that. I think we have come up with some 21 examples. I just want to preface, before we go 22 through the examples, in saying that this is one -- 45 1 the emphasis here should be working through the 2 process, not on specifically -- this is one example; 3 it is possible that another IRB could look at things 4 differently, but the thought here was to have you 5 begin to think through the principles and the process 6 that you would arrive at. And I have to say that when 7 I did some examples at Columbia, it was like light 8 bulbs, "Oh, this is what you mean by this." "This is 9 how you apply it." So, please think of that as we go 10 through the examples. You may or may not agree with 11 some of the decisions made in the examples, but it is 12 there to go through the process. So, that is a 13 preface to that. 14 This is really the category that is saying 15 that this is research, that there is greater than 16 minimal risk, using the definition that we previously 17 provided, that does not hold out a prospect of direct 18 benefit, but is likely to contribute to the well-being 19 of the subject, only if the IRB finds -- and these are 20 the four criteria that are straight out of the 21 Regulations and the words that are in red are the 22 words that we tried to really sort of "tease" apart 46 1 and we will go through that. We are going to go 2 through it exactly as it says. It says, "minor 3 increase," "commensurate," "disorder condition," 4 "vital importance." And then we will come back to 5 some examples to show how that flushes through that. 6 As a reminder, before we move forward on 7 this, to remember that this places a ceiling on the 8 level of risk and restricts the subject populations 9 that an IRB can independently approve. This does not 10 say if it does not meet these criteria, it cannot be 11 done. What it is saying is, "This is where an IRB has 12 to stop," and then it moves forward if it is Federally 13 funded to a 407 review process that we have talked 14 about. 15 Studies which do not qualify for approval 16 under 406 can be approved under 407, and here is the 17 criteria. "It poses more than a minor increase over 18 minimal risk without the prospect of direct benefit 19 for children with a disorder or condition or involve 20 a healthy control that does not have a condition which 21 qualifies for the purpose of the research." We will 22 get back to that healthy control issue because that 47 1 was something that came up last time, did we 2 completely want to wipe out all healthy controls, and 3 I think we have done the best job as we can because I 4 think you will see that there are some situations 5 where a healthy control really is being studied 6 because of a condition, and that will become clearer. 7 So, let us start with "minor increase over 8 minimal risk." This was the thing that we had ten 9 different Recommendations on and everyone, sort of, 10 almost jumped off their seat -- I know Ada Sue did ¦ 11 "Oh, my gosh, you know, my IRB just cannot do that." 12 Basically, what we worked through and 13 tried to simplify it is that, first of all, a minor 14 increase -- the first part is obvious, if it does not 15 meet the minimal risk criteria -- so, it falls outside 16 of what we just discussed. However, what the 17 investigator would need to do is present sufficient 18 evidence, -- so we want this sort of evidence-based, - 19 - about the procedures, the population, the 20 qualifications of the research personnel, so we are 21 bringing in here this area of expertise, that all of 22 these things have to be included, -- and show that the 48 1 increase in the probability and magnitude of harm is 2 only "slightly" more than minimal risk. Now, we tried 3 very, very hard to try and further define what 4 "slightly more than minimal risk" means. We were no 5 more successful than the National Commission, NHRPAC, 6 IOM. And we came back to this, really to say that 7 what we really need to say is that this is just a 8 little bit more. We have gone through examples -- we 9 went the whole 360 degrees, if there is any way to do 10 this better -- and what we tried to do is then put in 11 some different caveats here, but we could not think of 12 a better way, except to say this is just, folks, "a 13 little bit more." If you folks have the wisdom to do 14 better with this, we will certainly expand on that. 15 But the important thing is -- the other thing is that 16 the potential for harm, what could happen if something 17 is slightly more than minimal risk, will be transient 18 and reversible. So it needs to be something that can 19 be -- in addition to being just a little bit more, 20 needs to be able to be transient and can be turned 21 around; that it is not going to be something -- that 22 there is no chance that something can be permanent. 49 1 This is where we go back to looking at sufficient 2 evidence. This is not just some investigator saying 3 that he thinks that there is evidence. The 4 qualifications of the researcher and the setting are 5 very, very important here. And that there is no, or 6 an extremely small probability, that participants will 7 experience pain, discomfort, stress or harm associated 8 with the procedure which is severe. What this is 9 really saying is that -- and this happens all the time 10 -- if you ask clinicians or investigators, they say, 11 "Of course, this is minimal risk in my terms. I can 12 do this. I do this all the time." But the part here 13 is to think about how our participant is going to 14 think about that. We can say that lumbar punctures 15 are -- the harms are transient, reversible, but is the 16 participant going to think about this as slightly, 17 just a little bit more than minimal risk. So, we 18 really tried to bring in, sort of, the participant's 19 side. Again, that is going to require sufficient 20 evidence. We are going to have to go back and be 21 convinced that it is just not the investigator saying, 22 "My subjects do real well. No one squirms or cries." 50 1 That this is something the way that is a good 2 experience. 3 Believe it or not, out of the ten 4 different categories that we had before, we came down 5 with, sort of, this is the recommendation for a minor 6 increase over minimal risk. 7 Okay, the term "condition," "The 8 intervention or procedure is likely to yield 9 generalizable knowledge about the subject's disorder 10 or condition, which is of vital importance to the 11 understanding or amelioration of the subject's 12 disorder or condition." So, I think we feel 13 comfortable with what a "disorder" is, but here we go 14 with this definition of what does "condition" mean. 15 What is a "condition"? Again, we looked at previous 16 work. We never really veered far from where the IOM 17 Report and the NHRPAC Report came out, but what we 18 have suggested here is that the term "condition" 19 should be interpreted as "relating to a specific or 20 set of specific physical, psychological 21 neurodevelopment or social characteristics that an 22 established body of scientific or clinical evidence" - 51 1 - and I underlined that because when we get through 2 some of the examples, you will see that there is a 3 difference between a body of scientific and clinical 4 evidence. Sometimes there is research that is done on 5 a hunch of clinical evidence. But what we are saying 6 here is that in order to be defined as a "condition," 7 there has to be some basis for that, either way, "has 8 shown to negatively affect children's health and well- 9 being or to increase their risk of developing a health 10 problem in the future." So, what we are saying here 11 is that it is going to negatively affect them 12 currently or potentially in the future. That really 13 gets to some of the predispositions to Diabetes, 14 predispositions to genetic disorders, that we can 15 think about that also as a condition, if there is 16 "sufficient scientific or clinical types of evidence." 17 I think what we are trying to avoid here is the term 18 that we often use, sort of, "putting kids at greater 19 than minimal risk, no potential for direct benefit for 20 a fishing expedition." There has to be some grounds 21 in there that this represents some type of condition. 22 Now, the concern -- and this was raised by 52 1 SACHRP last time -- if ten healthy children ever had 2 a condition -- I think we have tried to avoid being 3 "normal" as a condition -- and we wanted to address 4 this because this implication really -- there is lots 5 of research where we have to have certain types of 6 normal types of values, and will this, sort of, our 7 definition, wipe this out or can it be permitted. So, 8 what we have -- we have an example here of two healthy 9 populations, one of which it could be classified as a 10 condition and one, it could not. So, the first would 11 be, for example, healthy pre-school children may have 12 a condition for a study designed to test 13 immunogenicity of a potential vaccine for a common 14 childhood disease. So certain types of vaccine trials 15 when they just begin, when they are in the first 16 phase, where you cannot really argue that there is a 17 potential for direct benefit, you know, does this 18 child -- if you took normal children -- have a healthy 19 condition? What we are saying here is that because 20 children in general suffer certain types of common 21 diseases, that perhaps, in this situation, a child 22 would have, you know, a condition. But they would not 53 1 have a condition for a study testing the 2 pharmacokinetics of a drug for potential treatment of 3 a childhood Leukemia, because that is not something 4 that would apply to the general population of 5 children. So, we may want to, sort of, think about 6 this. I think this is one of the -- this is one of 7 the more difficult parts here to think about. But 8 here is an example where you do have children who are 9 normal, but a lot of what the condition is being tied 10 into is the purpose of the research and what it is 11 that you are studying. 12 "Living in an unsafe environment." This 13 was sort of our attempt to try and get at that. 14 "Healthy children living in areas where the risk of 15 serious disease or adverse life events of the child is 16 high, may be determined to have a condition for a 17 study designed to discover factors that may lead to an 18 increased understanding or amelioration of the 19 condition." We are still trying to think about how do 20 we think about "condition" and "children." For the 21 example here, you are doing research on a vaccine in 22 children where there is a high incidence -- in a 54 1 country where there is a high incidence of Malaria, 2 that that, presenting a minor increase over minimal 3 risk, which tests against immunogenicity of a 4 potential vaccine for Malaria, probably for children 5 in that area, that that could be qualified as a 6 "condition." Whereas, you would not want to take 7 children in an area outside -- an area where there is 8 Malaria, and use them for research. 9 The next category is "vital importance." 10 This is basically saying, from the Regulations, that 11 the intervention or procedure is likely to yield 12 generalizable knowledge, which is of vital importance 13 for understanding or amelioration of the subject's 14 disorder or condition. I always -- when I lecture 15 about this, I say, you know, there is no investigator 16 who does not think that his work, his or her work is 17 of vital importance, because what this is saying is 18 that the threshold for convincing the IRB has to be 19 higher. It has to be higher. 20 So, in thinking about how does an IRB 21 really determine -- what are the guidelines for 22 thinking whether something is of vital importance? 55 1 Well, first of all, there needs to be clear and 2 significant scientific evidence, and this has to be 3 evidence-based, that this is something that is very 4 important, and that generalized -- the evidence has to 5 be about generalizeable knowledge that would 6 contribute to understanding the etiology, prevention, 7 diagnosis, pathophysiology, amelioration or treatment 8 of the disorder or condition. This slide is sort of 9 set up funny. But really what the message is here is 10 saying that you need to have -- there has to be 11 evidence. The investigator needs to provide that and 12 the IRB has to agree to that. 13 A healthy comparison group approvable 14 under 406. So, here is an example of the research 15 designed to collect data that are vital to 16 understanding the comparison group's condition. So, 17 here is an example to try and help explain that. An 18 example might be the comparison of biological markers 19 in HIV positive and negative newborns whose mother is 20 HIV positive, if the research is also designed to 21 further understand factors contributing to the 22 neonates natural immune responses against maternal 56 1 HIV. So, here the condition of not being infected 2 with the HIV could be of vital importance. 3 An example, a healthy comparison group 4 that is not approvable under 406. So, the example 5 here would be that if there was research designed only 6 to answer a question of vital importance to a 7 population with a disorder or condition that requires 8 a healthy comparison group for scientific validity. 9 What this is saying is if you took a healthy 10 population and you wanted to compare it to a 11 particular group, the example would be a comparison of 12 brain activity response to Ritalin in children with 13 and without ADHD. This segment of the research, if 14 considered worthwhile -- what this is basically saying 15 is that this would not be approvable under 406. It 16 could be submitted under 407. 17 "Commensurate," really, was the last 18 definition. What do we mean by "commensurate?" The 19 group here ¦ SACHRP, I know the last time we talked 20 about "commensurate," "Does this apply specifically to 21 thinking about risks or the consent and assent 22 process?" And what the Regs guide us -- is that the 57 1 intervention has to present experiences that are 2 reasonably commensurate with those inherent in an 3 actual or expected medical, dental, psychological, 4 social or educational situation. What we have decided 5 here is really that the -- in looking back at what the 6 National Commission wrote in thinking about this, this 7 concept, is really that the commensurability 8 requirement really refers to ways for individuals to 9 think about deciding, for parents and children to 10 think about whether they can consent or assent to 11 this; that this is not an attempt to say if it is 12 commensurate, to make it more of a relative standard 13 with risks. So, "commensurate" should not be 14 introduced to the gauge of acceptable level of risks. 15 There are other conditions that address the risk 16 category and under 406, the level of acceptable risk 17 is determined by the definition of "minor increase 18 over minimal risk." That is where the "risk" part is 19 applied. What this basically means is that some 20 children will not be permitted under 406 to experience 21 that level of risk, even if it is a minor increase 22 over minimal risk. I think when we go through the 58 1 examples, it will, hopefully, be clear. 2 So, these are the four conditions. Let me 3 run through a couple of examples to see if this makes 4 any sense. One of the examples was in children who 5 are obese, who are at greater risk than normal 6 children for developing Type II Diabetes, so these are 7 children that are otherwise healthy, except they have 8 -- they are obese and there is scientific evidence 9 that this means that they are predisposed to Diabetes, 10 although they probably -- they do not have it at this 11 point. The researcher scientist proposes to examine 12 the time course and mechanism of insulin resistance. 13 So, he is looking about how and when the insulin 14 resistance changes, before it does, and these children 15 are otherwise healthy. What they propose to do is to 16 use an insulin clamp procedure that consists of, in 17 one arm, introducing through an IV, glucose, and in 18 the other arm, insulin and then looking at how that is 19 regulated. So, in this particular example, this would 20 be -- what, the example that we are trying to, sort 21 of, run through, thinking about greater than minimal 22 risk and no potential for direct benefit, and thinking 59 1 about those four conditions. 2 So, first of all, the criteria. Is this 3 greater than minimal risk? Let us suppose, and this 4 was information that was given to us by investigators, 5 that what the risks are are perhaps around one in 500, 6 include hypoglycemia, the blood sugar dropping, 7 dizziness, and fainting. There is, however, 8 consistent monitoring so that while the child is 9 undergoing this procedure, someone is carefully 10 looking and continuously looking at the imbalance; 11 that the nature -- let us say that this involves four 12 hours and two different lines. Do you agree that it 13 is greater than a burden in magnitude than insertion 14 of a single IV line. So, we might say that insertion 15 of a single IV might be minimal risk, but this really 16 is for a longer period of duration, that would bump 17 that out of a minimal risk-type category. Also, that 18 the injection of insulin, which is a pharmacological 19 active hormone, really would exceed the magnitude and 20 probability of harm, which may occur during a regular, 21 routine medical procedure. So, this is all sort of 22 criteria of why we would think that this is really 60 1 greater than minimal risk research. 2 Criteria Two would be that the 3 investigator has presented scientific evidence about 4 the procedures, populations, and qualifications of the 5 research personnel. So, once we have made that first 6 determination, now we need to look at sort of the 7 evidence base for this. And this might be an example 8 of the procedure, the dizziness, fainting, 9 hypoglycemia are only slightly greater -- I mean this 10 is where we tried to sort of think about what does 11 "slightly greater" mean, but based on the evidence, 12 then risk experience in daily life or during the 13 performance of routine examination or test for obese 14 children. There would also need to be adequate 15 measures in place to make sure that if the risk did 16 occur, that they would be transient and reversible. 17 So, the IRB would want to ask for a lot of information 18 about, "Well, what happens if there is hypoglycemia?" 19 "How quickly do you intervene?" "How quickly would 20 you know?" "What are the implications?" "How would 21 you reverse that?" So, that is applying that 22 criteria, now that it is transient and reversible. 61 1 The IRB would need to get information to be convinced 2 that, in that setting, with the experience, and 3 whatever, that those criteria could be met. And there 4 would also be evidence supporting the investigator's 5 claim that there is an extremely small probability 6 that distress, discomfort, pain, or harm occurred by 7 dizziness, fainting, as it would be experienced by the 8 subjects, will not be severe. So, again, this is the 9 part that not only would the investigator say, "Well, 10 this is not severe," but there would have to be 11 evidence to say that the population who has had this 12 done does not experience this as severe. 13 The third thing would be that the subject 14 population has a condition. The investigator would 15 have to provide epidemiological information that obese 16 children are at risk for becoming Diabetic. This 17 would avoid sort of what I was referring to as a 18 "fishing expedition." There would have to be data 19 there that would suggest that. 20 The fourth criteria is that the research 21 is of vital importance to obese children as a class. 22 The investigator would need to explain and convince 62 1 the IRB that the development and testing were 2 appropriate interventions, prevent the onset of 3 Diabetes in obese children, you need to have this 4 data, that this is data that will be put to use for 5 this particular population in the future, and that the 6 data emerging from use of this clamp study are likely 7 to yield generalizable knowledge that will contribute 8 to the understanding of the prevention of Diabetes in 9 obese children. This delves into the science of the 10 information that you are receiving and that it is 11 vitally important to develop future prevention models 12 or treatment models for this. 13 The procedure is commensurate with those 14 inherent in the subject's actual or expected medical 15 situation. This would be criteria 5. An example 16 would be that children, as a class, have experience 17 with medical procedures similar to intravenous 18 infusions, might be injections or blood tests, and 19 that obese children, as a class, are at risk of 20 Diabetes and with the onset of Diabetes, it is 21 suspected that they will have insulin infusion. So 22 this is how we are trying to think about the 63 1 commensurability. 2 So, perhaps with obese children, I think 3 what this is suggesting is that this particular 4 design, with enough information, would satisfy the 5 criteria of greater than minimal risk without a 6 potential for direct benefit. That is what sort of 7 the point is of how the criteria works through. 8 Now, let us say that the investigator 9 proposes to add a complete healthy, non-obese 10 comparison group. How would those same criteria work 11 through? The first question, "Is it a minimal risk 12 procedure?" I think there would be no difference here 13 for children who were obese or normal. We came up 14 with a determination that it was not minimal risk and 15 that would apply here, that, no, it is not minimal 16 risk. "Is the procedure a minor increase over minimal 17 risk?" Again, I think, -- yes, it is the same 18 criteria. There would be nothing different here for 19 the two different populations. So, perhaps the first 20 two criteria could be met. "Do average weight 21 children have a condition?" I think this is where we 22 would vary and think differently, that, no, average 64 1 weight, healthy children are not at risk for Diabetes; 2 therefore, they do not have a condition. What we 3 would suggest here is that the IRB could not approve 4 this in the inclusion of the comparison group under 5 406; that this would not be permitted under 406; not 6 that it should not be done, but that this would 7 qualify for a 407 review. 8 So, the Example 3 is building on this to 9 present, sort of, a different way of thinking about 10 it. Let us say that clinicians have reported that 11 Autistic children -- and this is all hypothetical -- 12 with Diabetes, have mood swings that may be associated 13 with blood sugar levels that are more variable than 14 observed in normal children. So, an investigator is 15 proposing, based on some evidence, that they want to 16 do this with Autistic children. And that the first 17 step to do this is to do the insulin clamp study and 18 the research scientist proposes to examine the time 19 course and mechanism of insulin resistance using the 20 same procedure. So, how would we think about that 21 with the criteria? "Is it minimal risk?" No, that 22 does not differ depending on what the child has had. 65 1 "Does the procedure present only a minor increase over 2 minimal risk?" Here, really is where it would differ. 3 We could argue that it is only slightly greater in 4 magnitude. We could argue that the measures are 5 transient and reversible. But, is there empirical 6 evidence suggesting that there is a small probability 7 that Autistic children who would find restraints and 8 invasive procedures highly stressful, would experience 9 this as severe? So, this is an example of, because of 10 the child, where in the other situations, children may 11 not experience this as severe, in this particular 12 situation, we would say yes. This criteria could not 13 be met. Because of the nature of Autism and 14 restraints, this would be considered to be experience 15 severe and it could not be permitted, even though 16 there may be evidence, for example, to say that this 17 is a particular issue that needs to be studied. There 18 may be scientific evidence. Again, it is not saying 19 it cannot be done; it is just saying that under 406, 20 under those criteria, that it would be very difficult 21 for an IRB to approve that. So, in this particular 22 case, we would say that the IRB cannot approve that. 66 1 So, I am going to stop there. I know that 2 this is a lot of information. I do not know how you 3 want to go back and sort of talk about the different 4 definitions or the examples, or whether you want to 5 talk a little bit about the definitions first and then 6 go back to the examples. It is open for discussion. 7 CHAIRMAN PRENTICE: Mark? 8 MS. KORNETSKY: Mark? 9 MR. BARNES: I still have a problem with 10 "commensurate" and I know that I have raised this 11 before. You know, when you look at "commensurate," 12 and you look at your example about actual and expected 13 -- and remember, these are children who are obese and 14 at higher risk for developing Diabetes and if they had 15 -- and so the reasoning, according to your example, if 16 that they had Diabetes, then in the future, they would 17 have injections, right? 18 MS. KORNETSKY: Yes. 19 MR. BARNES: So, therefore, it would meet 20 the implied -- meet the commensurability test. But is 21 seems to me -- the more ¦ you know, it is hard. I 22 would like the criterion to be able to be interpreted 67 1 the way that you guys have done it, and I know that 2 there is sort of legislative history about what the 3 National Commission meant, but it is a problem when, 4 like, a Legislature says that it is doing one thing 5 but the words of the statue say something else. When 6 it says "commensurability of risks" and then when it 7 even goes further and says "commensurability of 8 expected risks," and the fact that "expected" is in 9 there, it means that it has not happened yet and it 10 might, seems to undercut the idea that they would 11 actually even know what the risks were about, which 12 leads me to think that, you know, I get back to the 13 point that "commensurability" to me -- I mean, if you 14 just read it, without the gloss of the legislative 15 history, or you know, the National Commission history, 16 it is what it says, and it just -- I would like to, 17 like I say, I would like to believe the way that you 18 believe, and that would certainly be an easier way to 19 apply the criterion, but I just do not think the 20 language says that, and the fact that the "expected" 21 thing is in there, I think undermines the point that 22 it is really about what they are familiar with. 68 1 Because they are not familiar with it yet. These kids 2 have not had injections like that yet. 3 MS. KORNETSKY: I cannot agree with you 4 more, and I have to say that, you know, the 5 Subcommittee, if there was one part of the children's 6 regulations that the Subcommittee really had a problem 7 with and said, "Can we throw something out?" or 8 redesign it or whatever, this was it. I think what we 9 tried -- because your concerns of "expected" and what 10 does that mean, that was put in there -- if you read 11 the National Commission's Report, it does not 12 necessarily refer to "expected," it sort of comes in 13 later. So, there must have been something going on 14 with drafting the Regs, with the National Commission's 15 Report, to put that in. So, I think if we could sort 16 of throw everything out and say, "What do we mean by 17 `commensurability'?" we would probably recommend a 18 change in the Regulations in this part. 19 There was just no way around that. I think what we 20 tried to do, the best we can, is to work around that. 21 And I agree with you; I do not think there is any 22 Subcommittee member that would say, "This is not a 69 1 real problematic part of the Regulations." I mean, I 2 do not know how we could make it better. The words 3 are there. You know, we cannot say, "Let's remove the 4 `expected'" because it will make it a lot clearer. 5 The words are there. So, that is a real challenge. 6 Susan? 7 DR. WEINER: To follow-up about that, I 8 think that in the examples and explanations that are 9 given, that very confusion still holds. For example, 10 on Slide 22, the reason that it is unacceptable to 11 give kids, normal kids -- to study the 12 pharmacokinetics of a drug for Leukemia in normal 13 kids, is not because the kids are normal, but because 14 the thing being studied is unacceptably risky because, 15 by the same standard, these children are normal and, 16 therefore, the probability of their getting Leukemia 17 perhaps is lower than those kids who were likely to be 18 obese, but nonetheless, there is a certain 19 probability. So, I think that, you know, we need to 20 sort of clarify that example. And, so, too, when on 21 Slide 38, where -- Criterion 5, where you discuss the 22 situation about obese kids, here, it is clearly 70 1 another example of how "commensurate" slides into 2 "relative." Earlier on, Criterion 5 really is 3 interpreted in terms of consent and assent and here, 4 the explanation that is given has nothing to do with 5 consent or assent. Rather, it is given -- the 6 explanation is given with respect to the class of 7 kids, of obese kids, being at higher likelihood for 8 Diabetes. So, you know, if we really believe that 9 "commensurate" -- if we really would like to shape 10 opinion so that "commensurate" has to do with consent 11 rather than with a relative standard, we really have 12 to push it harder, because it is not really clear. It 13 is also not clear in the definition -- and forgive me 14 -- here it is -- in the definition of "commensurate." 15 It says, -- you know, again, it is circular -- 16 "¦reasonably similar to those procedures that children 17 with a condition or disorder as a class have or are 18 expected to have." So, you know, one solution is to 19 agree on the intent, the Subcommittee's intent, and 20 then to change the text of these examples. 21 MS. KORNETSKY: I want to make sure that 22 everyone sort of agrees with the intent because, I 71 1 mean, there has been some discussion there. I think 2 the Subcommittee felt very comfortable with the intent 3 really being that people are familiar with. I have to 4 say that we have to think of the implications of that 5 for the types of research that would fall under 406 6 and others that would need to move to 407. I am not 7 saying that is a bad thing. We have done a lot to 8 improve the 407 process, but there are some very 9 practical implications that would then bump a 10 proportion of research into the 407 category, which -- 11 I just want to make people aware of that. I am not 12 saying, you know, that is a good or bad thing. 13 DR. WEINER: I can only say that given the 14 opportunity to do more aggressive testing on kids that 15 have a disorder or condition, the justification always 16 is, well, it will help those children. But, indeed, 17 it is contradictory to the notion that it would not 18 apply an additional burden, research burden. 19 MS. KORNETSKY: Good comments. Ernie, do 20 you have anything to -- to sort of -- this is a tough 21 one. 22 CHAIRMAN PRENTICE: Yes, as Susan 72 1 indicated, the Subcommittee spent an awful lot of time 2 talking about this and I think it -- you know, 3 philosophically, it would be nice to restrict 4 "commensurability" to only those procedures which a 5 prospective research subject has actually experienced. 6 That is not in the Regulations. It was not, of 7 course, in the National Commission's Report, they did 8 not address this, but the framers of the Regulations, 9 and I have not gone back to look at this in the 10 Preamble, but they clearly felt that they needed to 11 have some flexibility relative to procedures that 12 would be approvable under 406 and they did not want to 13 restrict that to only those procedures a child would 14 have experienced. So, that is the reason for 15 "expected." But it has got to be equivalent in terms 16 of risk. I think that is the key that we need to 17 focus on. It does not open up the door to allow any 18 procedure that might occur sometime in the future. It 19 is really restricted. So, I guess, Susan, I am not 20 quite as concerned as you are -- and Mark as well, 21 about that particular aspect of "commensurability." 22 MS. KORNETSKY: Some of the discussion 73 1 about what could have been, you know, thought about 2 with adding the "expected" is that even among -- if 3 someone has a predisposition, that there may be 4 knowledge being shared with other people or other 5 populations of patients of, sort of, what it is that 6 they are expected to undergo. This was some of the 7 thought that -- you know, support groups or whatever, 8 maybe another child -- that there would have to be 9 some basis and perhaps that is why when they say 10 "expected," it is not totally irrelevant; that they 11 have some knowledge of that. It is true it may not 12 have been something that they and their child have 13 agreed to that they have given permission for, but it 14 is not something that is totally foreign to them. It 15 is something that is very likely to have and they may 16 have information about what that is going to involve 17 when their child reaches that level. 18 CHAIRMAN PRENTICE: And I think it is 19 important to remember that in terms of the risk level 20 associated with the actual or expected procedure, it 21 is only slightly more than minimal risk. That is a 22 really key point. We are not talking about a dramatic 74 1 increase in risk here. We are talking about only 2 slightly more than minimal risk and we really have a 3 rather low threshold for minimal risk utilizing the 4 Uniform Standard. 5 MS. KORNETSKY: And I think we have to 6 remember that all four of these independently have to 7 be very clearly satisfied. 8 MS. KORNETSKY: Mark and then Susan -- 9 Susan, did you ¦ 10 MR. BARNES: Go ahead, Susan. 11 DR. WEINER: I think that it is a question 12 of the definition of the class. That is, how you 13 define the class, the research class, the subject 14 class. It determines whether or not you have a 15 relative or an absolute standard. So, if you define 16 the class as "children with Diabetes" as opposed to -- 17 if that is the standard against which you are judging 18 the commensurability of this study, then it gives you 19 -- you know -- I am sorry -- I am on the other side 20 of this issue, as you well know. It seems to me that 21 one has to use the absolute standard regardless, and 22 I just would hate to have us, as a Committee, 75 1 recommend that "commensurability" implied, however we 2 stated it, a relative standard for a subject 3 population. 4 MS. KORNETSKY: Mark? 5 MR. BARNES: You know, I am just-- this is 6 all -- I mean, I think about this differently every 7 time we talk about it. But I come back to what Ernie 8 said, and what you just said -- what this Susan said - 9 - because these are independent criteria. So, it has 10 got to meet the objective standard of only "minor 11 increase over minimal risk." Right? 12 MS. KORNETSKY: Absolutely. If it does 13 not meet that, then these things are irrelevant. 14 MR. BARNES: Then everything else is 15 irrelevant. You never get to the "commensurability" 16 issue. So, if it is a minor increase over minimal 17 risk, then if one reads the "commensurability" as a 18 subjective standard, it seems to me that the only 19 thing that is going to do is actually increase 20 protection because -- in other words, not reading it 21 as "assent/consent," but just reading it as a sliding 22 scale based on that child's particular circumstances, 76 1 then even if -- if the child -- let me give you a 2 couple of examples. If the child has all sorts of 3 conditions and, therefore, is accustomed to 4 experiencing lots of different, you know, diagnostic 5 procedures and everything else, well then, if you 6 interpret it that way, to bring in that child's 7 subjective experience, you still cannot go forward 8 because you are not going to meet the minimal increase 9 over -- the minor increase over minimal risk. So, it 10 is not going to have -- in the wash, it is not going 11 to dilute protection, one could argue. Whereas, for 12 the child who had never been subjected to anything, it 13 might be a minor increase over minimal risk, but if it 14 is not commensurate with that child's experience, then 15 it would not be allowed to go forward under 406, based 16 on the "commensurability." So, my point that I am 17 trying to make is that if you accept 18 "commensurability" as a sliding scale and not as the 19 "assent/consent," then I do not really think that it - 20 - I think that it only heightens protection and not 21 dilutes protection. Does that make sense? 22 MS. KORNETSKY: Yes. I think I hear what 77 1 you are saying. I think all of these things, you 2 know, once you -- if an IRB was convinced that 3 something was just only slightly more, as you go 4 through these independent things, it does become more 5 protective, and it does knock out certain types of 6 groups where it would permit it in the other types of 7 groups. So, again, the only way that I sort of 8 personally felt comfortable trying to think about this 9 is continually reminding myself, this is, like Ernie 10 said, this is just a little bit more. This is not 11 really risky research. This is just a little bit 12 more. 13 MR. BARNES: It may be important in your 14 final report -- it is important in your final report, 15 I think, to -- whatever we all agree that the 16 recommendation is going to be and what you guys decide 17 about "commensurability," it is very important to 18 stress that these are all independent variables and 19 that you cannot read "minor increment over minimal 20 risk" to be modified by B, right? 21 MS. KORNETSKY: That is correct. 22 MR. BARNES: Okay. I just think you need 78 1 to stress that. 2 DR. WEINER: I think they are sequential. 3 Is that not what you said? I think the decisions are 4 sequential. 5 MS. KORNETSKY: Well, I think -- we have 6 given some thought about having the condition -- the 7 way that they are written in the Regulations, they are 8 not sequential. I mean, I think we can think through 9 -- are there even more heightened protections now, if 10 they are sequential. I think the end result is 11 probably going to be the same. They all have to be 12 independent. One cannot depend on the other. You 13 cannot say, "Well, okay this is a minor increase over 14 minimal risk because it is of vital importance or it 15 is commensurate." They all have to be independently 16 justified. 17 Nancy? 18 DR. JONES: May I say something? Susan, 19 this is a lot easier to follow and I think it works. 20 Maybe with a little tweaking, but I think it is really 21 good. But the one area that I would struggle with -- 22 or just when you say "scientific evidence," and -- 79 1 "clear and significant scientific evidence," on Slide 2 25, and a couple of other places -- I like that you 3 use the words "a body of evidence" when you were 4 defining a condition so that it would be actually not 5 in just one paper, but out there in the general 6 consensus that it is there. But it is difficult 7 sometimes to weigh what is -- 8 MS. KORNETSKY: "A sufficient body of 9 evidence?" 10 DR. JONES: Yes, the main line scientific 11 evidence versus, wow, we have one new paper that is 12 really exciting and it seems like it proves that 13 point. 14 MS. KORNETSKY: Right. Well, you know, it 15 is interesting because even the example we gave with 16 the insulin -- I mean, right now, we are sitting here 17 in hindsight, saying "obesity leads to Diabetes," but 18 if this same proposal was 15 years ago, we may not 19 have -- this may not have been categorized the same 20 way. 21 DR. JONES: Right. 22 MS. KORNETSKY: So, it is -- you are 80 1 absolutely correct. What is "a body of evidence?" I 2 think we are trying to avoid that, sort of, you know, 3 oh, one person all of a sudden comes up with an idea, 4 and that is going to really be a burden on the 5 investigator. I know we are going to have lots of 6 other discussions about investigator responsibility. 7 And if we can think of ways to sort of say that 8 better, but I think here, it is -- we are trying to 9 really impress that it is not just someone's brainy 10 idea of one evening and they go forward with it. 11 There has to be something behind that. 12 DR. JONES: The one other thing that 13 occurred to me, too, I think -- it is not really in 14 the human subject -- or correct me, Ernie -- but one 15 thing I liked from the animal is that you also have to 16 say that there is no other alternative procedures that 17 have less risk before you propose this particular 18 thing. But that is not really explicitly stated. 19 CHAIRMAN PRENTICE: That would be in 20 Subpart A where you are required to minimize risk, so, 21 while it is not specifically stated in Subpart D, it 22 would be inherent in Subpart A. You need to 81 1 substitute "procedures" with "less risk." 2 MS. KORNETSKY: It is also in 405. There 3 is something about alternatives as one of the 4 criteria, and I can give you a great example of 5 something that was bounced because of the alternative 6 thing. 7 Ada Sue, did you have a comment? 8 MS. SELWITZ: Well, and again -- I am not 9 sure it is a good one and that is why I hesitated, but 10 -- and we talked about this last time -- and I sit 11 here and try to think, can you have a greater than 12 minimal risk and have no direct benefit for a social 13 science study? Because all these examples are very 14 medically based, and I am sitting here trying to 15 apply these same criteria to a social science study. 16 And I certainly know that we have reviewed studies 17 that we considered greater than minimal risk that were 18 social science and not of direct benefit. I mean, 19 that is not that unusual in social science, that you 20 are not going to find a direct benefit. So, what I 21 would hope is that in the final report, there could be 22 an example of applying these criteria to not just 82 1 medically based studies, a social science study. But 2 I know we talked about this last time and the feel was 3 that you are not going to have a study that is greater 4 than minimal risk and not of direct benefit. 5 MS. KORNETSKY: I think you are right. 6 If you could share with ¦ I mean, we have, again, 7 looked at the make-up of the group, except with Celia 8 and a lot of her work is sort of also more 9 biomedically influenced -- if you could share a couple 10 examples of things, I think it is very important to 11 think it through, because what I want to avoid, as 12 with many things, is that we take a biomedical 13 approach and then it becomes completely unworkable on 14 the behavioral and social science sides. 15 MS. SELWITZ:And I will admit that I could 16 not sit here and apply these criteria in the social 17 science area. I thought about it on the plane 18 yesterday and tried to -- I can come up with the 19 examples, but when I start applying the criteria, I 20 have not had enough experience with your criteria as 21 yet, although, I am with Nancy. I think this is much 22 easier to follow than what we saw last time, or maybe 83 1 it is because it is the second time for me and it is 2 getting clearer. 3 MS. KORNETSKY: Let us talk. If you give 4 me some examples of protocols -- 5 MS. SELWITZ: I am hoping there are some 6 people in the audience as well, because I know several 7 of you were nodding your heads, good idea -- well, 8 help me out on this. I would be willing to give you 9 the kinds of examples I have been thinking about. 10 Where I get very shaky is trying to actually apply 11 these criteria to the examples. 12 MS. KORNETSKY: I think it is well worth 13 thinking that through as part of this. 14 CHAIRMAN PRENTICE: Yes, Ada Sue, I think 15 that is a very important suggestion because, 16 certainly, there are potentially studies in behavioral 17 social sciences that would qualify under 406. In 18 looking at the criteria, it seems to me that the most 19 problematic one might be "condition" as opposed to, 20 "Is it a minor increase over minimal risk?" "Is there 21 commensurability?" I think it really might be the 22 "condition." But that is certainly something that we 84 1 need to pursue. 2 MS. KORNETSKY: Ernie, how are we with 3 time? Continue, or -- 4 CHAIRMAN PRENTICE: Yes. We are doing 5 fine. We have 20 minutes before we take a break. We 6 can proceed with a -- if you want to -- 7 MS. KORNETSKY: Start with 405? 8 CHAIRMAN PRENTICE: Well, actually, maybe 9 we ought to ¦ maybe we ought to take a break and then 10 come back and go through the 405. 11 MS. KORNETSKY: And then go back? 12 CHAIRMAN PRENTICE: I do not think you can 13 get into the 405 before it is going to be time to take 14 a break -- 15 MS. KORNETSKY: Okay. 16 CHAIRMAN PRENTICE: I would hate to 17 interrupt that. 18 MS. KORNETSKY: Okay, that's fine. 19 CHAIRMAN PRENTICE: So, we will take a 20 break. We will come back and we will do the 405, and 21 then we will try to reach a consensus on the 22 Recommendations. 85 1 So, actually we are gong to take -- we are 2 scheduled for a 15-minute break; we will take 20 3 minutes. So, let us reconvene at 10:30 a.m. 4 (Whereupon, the above-entitled matter went 5 off the record at 10:10 a.m. and resumed at 10:30 6 a.m.) 7 MS. KORNETSKY: The next category that 8 perhaps has not been discussed quite as much, and 9 perhaps this is the easiest of the categories, but 10 there are some interesting sort of twists and ways of 11 thinking about things. It is the category of research 12 that presents greater than minimal risk. This goes 13 outside of even a minor increase. But there is a 14 potential for direct benefit to the individual. This 15 category, I think, is important because, from a very 16 practical sense, what IRBs do in order to avoid some 17 of the other things in 406 and 407, is that they 18 really sort of -- it is like a rubber band, they 19 really start stretching to make a case for potential 20 for direct benefits. So, although this seems like it 21 is kind of less controversial, it is as critical as 22 all of the other discussions, to think about how much 86 1 you can stretch and how you can do that. So that you 2 -- we do not want to have a situation where they are 3 stretching so much to try and avoid. So, that is this 4 particular category. 5 This is really ¦ this is really what this 6 category is. There are a couple of criteria that need 7 to be met. First is that the risk is justified by the 8 anticipated benefit, and we will talk about that. 9 Then the second part, which goes to what Tom raised, 10 about the alternative approaches, where does 11 "alternative approaches" fit in? Well, it fits in 12 right here. What has to happen, according to the 13 Regulations, is that when we think about the 14 anticipated benefit, the relation of that to the risk, 15 then it has to be at least as favorable to the 16 subjects as presented by available alternative 17 approaches. So, there is going to be a determination 18 here that even if you are proposing something greater 19 than minimal risk and there is a hope for potential 20 benefit, you have got to look at the alternatives. 21 And I will give you an example, although it is not 22 here, something that we have recently dealt with, to 87 1 show how this sometimes cannot be satisfied. Then we 2 have the adequate provisions for soliciting assent and 3 permission from the parents. 4 So, there are -- I think we came up with 5 six different proposals to think about in helping IRBs 6 think about the potential for direct benefit research. 7 Really, what we are saying, which I think is more 8 obvious, but important to start off in saying is that, 9 "When the research has a prospect of direct benefit, 10 that the ceiling of how much risk is determined by 11 whether it is appropriately proportional to the 12 probability and magnitude of the benefit." So, here, 13 we are using terms "probability" and "magnitude" again 14 to think about if there is a benefit, how often you 15 might think about it happening, and also, if it 16 happens, how significant that is. So, you need to 17 think about both of those things in thinking about a 18 potential for direct benefit. So, that is the first 19 proposal. It is really just expanding upon the idea 20 of sort of the sliding scale that as the risks go up, 21 the benefits really have to go up with it 22 proportionally, and thinking about probability and 88 1 magnitude. 2 The second part is dealing with the 3 alternative, available alternative, and really, this 4 is an additional protection because this is saying, 5 "Well, you could have something with great risk and 6 some benefit," but you need to look at what the 7 alternatives would be. So, as an additional 8 protection, even if the risks are balanced by the 9 benefits, a study may not be independently approved by 10 an IRB if the benefits are not at least as favorable 11 to the subjects as those presented in available 12 alternative approaches. Let me give