1 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES OFFICE FOR HUMAN RESEARCH PROTECTIONS + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTIONS + + + + + MEETING + + + + + Monday, October 4, 2004 + + + + + The Advisory Committee met in the Jefferson Ballroom in the Radisson Hotel Old Town Alexandria, 901 North Fairfax Street, Alexandria, Virginia, at 8:30 a.m., ERNEST D. PRENTICE, Ph.D., Chairman, presiding. MEMBERS PRESENT: ERNEST D. PRENTICE, Ph.D., Chair THOMAS L. ADAMS, CAE MARK BARNES, J.D., LL.M. CELIA B. FISHER, Ph.D. ROBERT G. HAUSER, M.D. NANCY L. JONES, Ph.D. FELIX A. KHIN-MUANG-GYI, Pharm. D. SUSAN KORNETSKY, M.P.H MARY L. POLAN, M.D., Ph.D., M.P.H. SUSAN L. WEINER, Ph.D. BERNARD A. SCHWETZ, D.V.M., Ph.D., Executive Secretary CATHERINE SLATINSHEK, M.A., Executive Director 2 EX OFFICIO MEMBERS: HOWARD L. BRADLEY, Social Security Administration KATHRYN LYNN CATES, U.S. Department of Veterans Affairs ROGER CORTESI, U.S. Environmental Protection Agency HELENE DERAMOND, U.S. Department of Education FRANK BRICKFIELD, Central Intelligence Agency SUZANNE GAYNOR, U.S. Department of Housing and Urban Development DAVID KLURFELD, U.S. Department of Agriculture DAVID LePAY, M.D., Ph.D., Food and Drug Administration AMY PATTERSON, National Institutes of Health DAVID SHORE, National Institutes of Health MICHAEL VIOLA, U.S. Department of Energy 3 I-N-D-E-X AGENDA ITEM PAGE Welcome: Opening Remarks 4 Ernest Prentice, Ph.D. Chairman, SACHRP Report on Issues 6 Bernard Schwetz, D.V.M., Ph.D. Director, OHRP Approval of Minutes from July 26, 27 Meeting 14 Overview of Charges to Subcommittees 15 Ernest Prentice, Ph.D. Chairman, SACHRP Public Comment 17 Report of Subcommittee on Research Involving 19 Children Dr. Celia Fisher, Co-Chair Susan Kornetsky, Co-Chair Report of Subcommittee on Researching 150 Involving Prisoners Mark Barnes, J.D., LL.M. Nancy Dubler Adjourn 272 4 1 P-R-O-C-E-E-D-I-N-G-S 2 (8:33 a.m.) 3 WELCOME: OPENING REMARKS 4 CHAIRPERSON PRENTICE: Good morning, 5 everybody. I think we will get started. My name is 6 Ernie Prentice. I am the Chair of SACHRP, the 7 Secretary's Advisory Committee for Human Research 8 Protection. I would like to welcome members of 9 SACHRP; ex officio members; and, most importantly, 10 members of the public. 11 You will note that we have a new logo. 12 Quite frankly, in my opinion, it is far better than 13 the last logo. I really, really like it. 14 As is our custom, we always begin with 15 reminding people of our charter. We are an advisory 16 committee that has been charged by the Secretary of 17 HHS to examine matters pertaining to protection of 18 human subjects with particular emphasis on special 19 populations who are vulnerable. And certainly the 20 work of the Committee reflects activity concerning 21 pursuit of that charge. We will talk more about that 22 in a moment. 5 1 Before we continue, I would encourage 2 everyone to turn their cell phones off, if you would. 3 These are the members of SACHRP. There is 4 one vacancy. And we are awaiting appointment of an 5 individual to replace Dr. Nigel Harris. 6 I would like to acknowledge the work of 7 Cathy Slatinshek, the Executive Director of SACHRP, 8 along with Kathy Booher and, actually, all of the 9 other members of the OHRP staff who have worked very, 10 very closely with members of SACHRP to accomplish what 11 we have accomplished thus far. So thanks very much, 12 Kelly and Cathy. 13 I also want to make a note that we also 14 work very closely with the Director of OHRP: Dr. 15 Bernard Schwetz. Dr. Schwetz has meetings regularly 16 with ex officio members of SACHRP to find out what are 17 their concerns. And those concerns are then, in turn, 18 brought to the attention of SACHRP. So we think that 19 that is a very, very important activity on the part of 20 OHRP and SACHRP. 21 Okay. Now I would like to turn the podium 22 over to Dr. Schwetz, who will give us a report on the 6 1 issues. Bern, would you like to do it from there? 2 EXECUTIVE SECRETARY SCHWETZ: Sure, if I 3 may. 4 REPORT ON ISSUES 5 EXECUTIVE SECRETARY SCHWETZ: Good 6 morning. Thank you, Ernie. And good morning to all 7 of you. For those of you who are wondering what 8 happened as of this week, the beginning of the new 9 fiscal year, we don't have a budget, but that doesn't 10 stop us from doing what we do in the federal 11 government. 12 We will be on a continuing resolution 13 that's approved at least until November 20th. The 14 expectation is that it will go on longer than that. 15 What it means is that you're kept to last year's 16 budget. And you can't start new major initiatives. 17 The concern is whether you get a release 18 from the continuing resolution in time to start new 19 initiatives, but at this point, things are going on as 20 we were last year. 21 The charter for OHRP has been approved 22 within HHS and is now at the Hill for final approval. 7 1 So I'm glad to have that approval through to this 2 level of approval. 3 There are two letters from SACHRP that are 4 in the Office of the Secretary, one that has to do 5 primarily with issues related to research involving 6 children. And the second one has to do with HIPAA 7 recommendations. So we're waiting to hear how those 8 are going to be handled and who will be working with 9 to get further feedback from the department's response 10 to the letters. 11 Regarding follow-up on Subpart B from the 12 last meeting, SACHRP requested that OHRP would develop 13 guidance on Subpart B that would address several 14 issues: one relative to social and behavioral 15 research that involves a woman who would become 16 pregnant during the study and the requirement that the 17 research leads to important biomedical knowledge that 18 cannot be obtained by other means. You also asked us 19 to develop information around the appropriate use of 20 exemptions that relate to pregnant women. So those 21 are issues that we're working on, and we hope to come 22 back to you by the next meeting with something 8 1 definitive. 2 I'm not sure I brought to the SACHRP the 3 fact that we have developed a fellowship program 4 within OHRP during this past year. And it now becomes 5 formal in '05, formal in the sense that it's a budget 6 item. We are interested in having fellows come in in 7 two different categories, in particular, one new 8 investigator so that we have the opportunity to have 9 new investigators come in and see what OHRP is like, 10 see what it's like to work in a regulatory office for 11 long enough to get a feel for what we do and to get a 12 better understanding of the regulations and the 13 process so that when they go back into their research 14 institution, they take with them knowledge of what it 15 means to know OHRP people and to know the regulations 16 and they know firsthand, instead of being afraid if 17 there is something in Washington that they know they 18 have to be scared of. So that would be one category. 19 The other one would be the people at the 20 other end of their career, in particular, who are the 21 notables in the field who probably are looking to 22 spend six months to a year on a sabbatical type of 9 1 stay. So both of these -- and we would be happy to 2 consider people in between as well, but we're looking 3 to bring people in to help us in our work but also to 4 bring in new perspectives, new ideas. 5 In '04, we have had three people come in. 6 We had a physician from Taiwan who worked for Melody 7 Lynn for several months to learn the U.S. position on 8 things. 9 Cathy Hanna is with us. She is a 10 consultant author on human subject protection issues 11 and has been working with the Department of Energy and 12 the IOM. She is now going to be helping us. 13 And Dr. Ivor Pritchard from the Department 14 of Education, someone who is recognized in social and 15 behavioral research and education-type questions, is 16 also with us on a dealt. 17 So we have had these two people who have 18 joined us now on a regular basis, Cathy not full-time 19 but Ivor full-time. They will be helping us, in 20 particular, to increase our capacity to write 21 guidance. I raise this with the hopes that you will 22 give us ideas of other fellows for whom it would be 10 1 beneficial to them and to OHRP to have them visit and 2 work with us for six months or a year, something in 3 that time frame. 4 I mentioned earlier that we were going to 5 work with IOM to develop a contract that had to do 6 with research in prisoners. Well, we now have a 7 contract in place with the Institute of Medicine to 8 form a committee to come up with the ethical bases for 9 conducting research involving prisoners. 10 So we're hoping to provide some guidance 11 in how a new Subpart C might look based on what the 12 ethics are for research involving prisoners as it is 13 today and that that precedent might be a basis for how 14 we would consider revisions to other parts of the 15 common rule in the future. 16 I also mentioned last time that we would 17 be raising the question of the priorities among the 18 agencies under the common rule, then the Human 19 Subjects Research Subcommittee of the Committee on 20 Science of NSTC, the National Science and Technology 21 Council. 22 We have been working for some time to look 11 1 at the priorities of the various agencies. And as we 2 made a final comparison of notes and discussion, it 3 came down to three general areas, three groupings. 4 The first one really is a collection of 5 things that have to do with confidentiality issues and 6 third party issues, mandatory reporting, under what 7 conditions when you are given information in the 8 study, is it mandatory that you report it to someone? 9 There are federal requirements. There are 10 state requirements. Well, they are poorly understood. 11 And there are times when you collect information that 12 has to do with drugs, with security. What do you do 13 with that information? And also another piece of that 14 is privacy related to genetic information. 15 A second category had to do with the 16 various issues that relate to multi-center trials, 17 including one that we are going to be talking about 18 tomorrow, central IRBs, but also the local context and 19 consistency of IRBs in how they do their job. 20 The third general area was international 21 research, lack of interest. Maybe "interest" isn't 22 the right word but the fact that social and behavioral 12 1 research doesn't get much attention at the 2 international level. And it probably should. 3 Research on rare diseases, hard to get 4 approval because if some research finds a patient in 5 a country where there may not even be a federal-wide 6 assurance in an institution, they're complaining that 7 other people get these patients into their studies 8 outside the U.S. and we don't have access to them 9 because of how we work; risks and benefits in the 10 local context and training and a number of other 11 issues. So those in general are the three things that 12 the Human Subjects Research Subcommittee came up with. 13 Regarding the meeting of the ex officios, 14 they continue to work in their effort to help us with 15 adverse event reporting and in the context of the 16 definitions and the terms bringing the two 17 dictionaries into a common set of definitions that can 18 be used to describe what the appropriate flow of 19 information should be and the sequence of steps that 20 are involved in adverse event reporting and also, a 21 very important task, identifying a standard format and 22 not just a standard format but content as well as 13 1 format for adverse event reports and also at a later 2 stage to deal with the question of how this 3 information will be made available to the appropriate 4 communities to have this information on what is known 5 about adverse events. 6 The ex officios are also in the middle of 7 discussing central IRBs, but I think at this point we 8 will wait and see what SACHRP is going to do with that 9 before the ex officios as a group decide what, if 10 anything, we should do about it. And also they're 11 interested in these priorities that are identified by 12 their counterparts in HSRS and setting our own 13 priorities. 14 The last thing I would mention is to 15 remind you of the commemorative event that we have 16 coming up on November 16th at 2:30 in the afternoon to 17 recognize and remember the 25th anniversary of the 18 Belmont report and to help raise awareness not only to 19 the Belmont report but the overall issue of ethics as 20 a basis for decision-making today. 21 So, Ernie, with that, I will quit. 22 CHAIRPERSON PRENTICE: Thank you, Bern. 14 1 APPROVAL OF MINUTES FROM JULY 26, 27 MEETING 2 CHAIRPERSON PRENTICE: I would like to 3 begin with a motion to approve the minutes from the 4 last meeting. Mark? 5 MEMBER BARNES: Move. 6 CHAIRPERSON PRENTICE: Second? 7 MEMBER HAUSER: Second. 8 CHAIRPERSON PRENTICE: Any further 9 discussion? 10 (No response.) 11 CHAIRPERSON PRENTICE: All of those in 12 favor? 13 (Whereupon, there was a chorus of 14 "ayes.") 15 CHAIRPERSON PRENTICE: Any opposed? 16 (No response.) 17 CHAIRPERSON PRENTICE: Any abstentions? 18 (No response.) 19 CHAIRPERSON PRENTICE: The minutes are 20 approved. 21 OVERVIEW OF CHARGES TO SUBCOMMITTEES 22 CHAIRPERSON PRENTICE: I would like to 15 1 once again provide an overview of the charges to our 2 SACHRP subcommittees. As you know, some of the 3 charges evolve as we accomplish certain goals. 4 The first charge concerns the Subcommittee 5 on Research Involving Children. You have all seen 6 this slide before. I show it because it depicts how 7 vulnerable kids can be. This is obviously Baby Faye, 8 who underwent the world's first xenotransplantation 9 involving a neonate on October 26th, 1984. 10 Now, the Subcommittee on Research 11 Involving Children has already developed 12 recommendations concerning how the 407 panel review 13 process ought to be structured in order to achieve 14 efficiency, ethical validity, and scientific validity. 15 As Bern mentioned, that letter has gone to 16 the Secretary. And we are optimistic that it will 17 result in official OHRP guidance sometime in the near 18 future. 19 In the meantime, the committee continues 20 to work on the interpretation of Subpart D, which I 21 think is really probably the meat of the task. And 22 that is really a tough charge to fulfill. 16 1 The co-chairs are Celia Fisher and Susan 2 Kornetsky. And they work the subcommittee. They meet 3 regularly in Washington. And they produce a series of 4 reports. You have a report in front of you this time, 5 and you are going to present to SACHRP the results of 6 your latest work. 7 The second subcommittee that is 8 operational is the Subpart C Subcommittee. The charge 9 for that particular subcommittee is to provide 10 recommendations for consideration by SACHRP on the 11 interpretation, reinterpretation, and then ultimately 12 we hope that that is going to lead to a revision of 13 Subpart C. 14 As Bern indicated, OHRP has already 15 contracted with the IOM to develop some guidance 16 concerning the ethical basis upon which such revisions 17 of the regulation should occur. 18 So the committee is primarily working on 19 what we would refer to as a short-term fix, come up 20 with guidance right now that will help IRBs cope with 21 Subpart C, which is clearly out of date and needs to 22 be revised. 17 1 The two co-chairs are Mark Barnes and 2 Nancy Dubler. They will present a report to SACHRP 3 following the Children's Subcommittee report. 4 All right. Now, what are we going to do 5 today? We have really an ambitious agenda, both for 6 today and for tomorrow. We have already gone through 7 the welcome and opening remarks, and Bern has reported 8 on the issues. I have given you an overview of 9 charges to the subcommittee. 10 PUBLIC COMMENT 11 CHAIRPERSON PRENTICE: We do have a 12 comment period for the public. I would like to ask, 13 anybody that is a member of the public, would you like 14 to express some views to SACHRP because we have no one 15 on the list at this particular point in time? 16 (No response.) 17 CHAIRPERSON PRENTICE: If no one steps up 18 when we get to the public comment period, then we are 19 simply going to move on to your report. But let's 20 continue. 21 From 9:30 to 10:30, we will have the 22 report of the Subcommittee on Research Involving 18 1 Children. We are going to take a break 10:30 to 2 10:45. Then we will continue with the Subcommittee 3 Involving Children from 10:45 to 12:00. 4 Lunch will be from 12:00 to 1:00. And for 5 those of you who have attended these meetings before, 6 you know that we do try to keep them on schedule as 7 much as possible. 8 From 1:00 to 3:00, the report of the 9 Subpart C Subcommittee will be delivered. We will 10 have a break between 3:00 and 3:15. 3:15 to 3:45, we 11 will simply discuss Committee business, whatever that 12 happens to be. 13 We will have another slot for public 14 comment between 3:45 and 4:15. Then between 4:15 and 15 5:00, we will have summary of the day's activities. 16 Then we will try to adjourn on time at 5:00 o'clock. 17 Okay. Now, this was the time for the 18 public comment period. Anybody from the public who 19 would like to address SACHRP? 20 (No response.) 21 CHAIRPERSON PRENTICE: Hearing none, we're 22 going to move on to your report. 19 1 REPORT OF THE SUBCOMMITTEE ON 2 RESEARCH INVOLVING CHILDREN 3 MEMBER FISHER: This is our fourth report 4 that Susan and I are presenting to you. I think the 5 best thing to do is to go by the PowerPoint, not by 6 the minutes. And you just got a copy of the 7 PowerPoint, I think, because as we were going over 8 this for the PowerPoint presentation, we tried to 9 organize it in a way that expressed the logic of the 10 committee meeting. 11 I wanted to remind you -- well, first let 12 me just mention we once again have an incredibly 13 wonderful committee, which includes Susan Weiner and 14 Susan Kornetsky from our group. And OHRP staff has 15 been absolutely incredible, as usual. We do get 16 excellent participation from those who come to sit in 17 at the meeting, and I think we really benefit from it. 18 The meeting goals are the same. And it is 19 that we are attempting over the course of this period 20 to clarify and help reach some consensus on Subpart D 21 regulations. 22 Now, the focus of our last four meetings 20 1 has been on non-beneficial research. And throughout 2 the course of this PowerPoint, I think we have used 3 "non-beneficial." I don't know what the appropriate 4 term is. So given everything has a scientific benefit 5 and the probability of benefit but just this 6 shorthand, that is the term we are using. But I want 7 to recognize the problems with that. 8 Now, there are two non-beneficial research 9 groupings under Subpart D that we have been focusing 10 on in order. The first is minimal risk. The second 11 is minor increase over minimal risk. They're 12 interrelated and determine the overall adequacy of 13 Subpart D. 14 I wanted to remind you that at the last 15 SACHRP meeting, SACHRP contingently approved the 16 uniform definition of minimal risk, which I am going 17 to go over, but I just wanted to remind you. 18 I think we are also thinking that based on 19 SACHRP's comments from last meeting as well as our own 20 continued deliberations on the Subcommittee, that we 21 would really like you to think carefully about 22 contingently approving the recommendations that relate 21 1 to minimal risk that I am going to go over in the 2 first part today because without knowing whether or 3 not this contingent approval for the way we are 4 looking at minimal risk, we can't really make any firm 5 conclusions about minor increment or all the standards 6 that go. 7 So as I make the first part of the 8 presentation, think about where you can or cannot feel 9 comfortable contingently adopting our recommendations. 10 And then I think, Ernie, it is approvable by you that 11 we stop after minimal risk, discuss those elements, 12 and then go on to minor increment, minor increment 13 being I think at this point much more challenging and 14 needing guidance. Now, that may only be because we 15 have had one meeting on minor increment or two 16 meetings, but who knows? 17 Okay. So we are going to start with 404, 18 which is minimal risk research. I am going to review 19 some of what I said last meeting, but I have tried to 20 shorten it. So I think the issue here is that 21 research without any probability of direct benefit for 22 the subjects involved is permittable with children 22 1 under 404 if it is of minimal risk and if, in fact, 2 adequate provisions have been made for -- is it not? 3 It doesn't have everything? Okay. Thank you. 4 So I think the issue we have to think 5 about here is this is the first entry into being able 6 to do non-beneficial research with children. The 7 criteria are that it has to be of minimal risk and 8 that adequate provisions are made for parental 9 permission and child assent. 10 The key here is that the only protections 11 other than defining minimal risk are the parental 12 permission, child assent. So this is an important 13 gateway into doing research that does not have direct 14 benefit to the participants. 15 So the question that we mentioned last 16 time is whether or not we should be looking at the 17 definition of minimal risk from a uniform or relative 18 standard. The phrase that is used is "Do risks 19 ordinarily encountered in daily life or the routine 20 physical or psychological examinations or tests," 21 which is in the definition of minimal risk in Subpart 22 A, "refer to a uniform standard," which would be the 23 1 same standard for everyone? 2 And, as you know, we are going on to say 3 that everyone has to be the average normal healthy 4 child living in safe environments or a relative 5 standard, that the risk is minimal to the kinds of 6 risks that the child faces in his or her routine 7 examinations or daily life. 8 The history of the definition is very 9 interesting because throughout the comment period and 10 through the national commission and Subpart C, there 11 was the notion of a uniform standard. I've listed all 12 of those things for you here, but you can see uniform 13 being healthy individuals, healthy persons, healthy 14 children. 15 However, in 1981 or perhaps a little bit 16 before, there was a shift to the relative definition. 17 And these are some of the aspects that indicated the 18 shift. First of all, because there was going to be a 19 Subpart A, the definition of the term "research" and 20 definition of the term "minimal risk" were removed 21 from Subpart D. Now, recall they are still in 22 independently in Subpart C. 24 1 Then there was a phrase that said, "In 2 light of the public comments, HHS has reworded the 3 final regulation," which is Subpart A, "to reflect its 4 intention that the risks of harm ordinarily 5 encountered in daily life means those risks 6 encountered in the daily lives of the subjects of the 7 research. 8 So, all of a sudden, in response to public 9 comment, which I am not sure exactly what all of that 10 comment was, there was a shift to a relative standard. 11 Now, what we also find very interesting is 12 so this is now the phrasing that is supposed to 13 reflect this relative standard in Subpart A. However, 14 please note there is nothing there that indicates it's 15 a relative or a uniform standard. 16 So I don't know if that was intentional 17 because the committee had or HHS had problems with 18 either uniform or relative, even though it is in the 19 preamble, but it certainly has created problems for 20 IRBs in terms of whether or not a uniform or relative 21 standard is being met. 22 Okay. So what are the arguments for or 25 1 against uniform versus relative standard? The justice 2 arguments for a uniform standard is that when there is 3 research that offers no probability of direct benefit, 4 children should not be subjected to greater research 5 risk simply because their daily lives are filled with 6 additional risk or harm. 7 The justice argument for the relative 8 standard is that children whose daily lives are filled 9 with greater risk should not be deprived of research 10 that is non-beneficial but will add to the knowledge 11 base for their lives. 12 Now, the committee, as we mentioned last 13 time, believed that, at least for 404, which is 14 minimal risk research, the justice argument is based 15 on a false assumption for the relative standard. That 16 is, a uniform definition will not deprive less healthy 17 children or less advantaged children from 18 participating in research. 19 These children can participate in 20 higher-risk studies that offer the possibility of 21 direct benefits, which is 405, that are likely to give 22 generalizable knowledge about the child's disorder or 26 1 condition, which is 406, or to provide opportunity to 2 understand, prevent, or alleviate a serious problem 3 affecting health or welfare of children under 407. So 4 there are other regulations that permit non-beneficial 5 or beneficial research for children that have a 6 disorder or a condition. 7 So what, then, is the rationale for the 8 uniform standard? Well, first we went to issues of 9 beneficence and non-maleficence. One of the issues 10 is, as I mentioned before, 404 is the critical 11 baseline. It's the gateway for approval of 12 higher-risk, non-beneficial research involving 13 children because 406 indexes minor increment to 14 minimal risk. So our notion is that we must be most 15 conservative at the 404 given that's the baseline for 16 which children can be included in non-beneficial 17 research that offers some element of risk. 18 In addition, as I mentioned before, there 19 is really no other protection other than parental 20 permission and child assent under 404. So it's 21 important that IRBs have some sense of and a national 22 consensus, if possible, but to the degree something to 27 1 reference to on an overall basis about what we mean by 2 "minimum." 3 And assent does not offer the same type of 4 protections as adult consent. Children don't have the 5 adult legal status to give consent. They don't have 6 the cognitive maturity in most instances except 7 perhaps in mid to late adolescence. And even in mid 8 to late adolescence, they don't have the experience or 9 authority of decision-making. 10 So IRBs in some sense have to play a very 11 significant role, as they always do, but cannot rely 12 simply on parental permission and child assent to 13 protect the child from minimal risk research that is 14 not appropriate. 15 The justice argument, as we mentioned 16 before, is approval of procedures as minimal risk 17 should be equally applied to all children with the 18 protections that accompany the level of risk 19 assessment. 20 Okay. So what we contingently approved 21 last time by SACHRP was that a uniform standard for 22 the definition of minimal risk be adopted for research 28 1 involving children under Subpart D. 2 Okay. Now, all of this, of course, 3 relates to a number of other proposals that we have 4 considered because uniform, in and of itself, is 5 really not very useful if there is not an index or 6 some way of saying, "Well, what do you mean by 7 'uniform'?" So we have attempted to come up with 8 relying on NHRPAC and the IOM reports as well as other 9 committees that have worked in the past. 10 So we are proposing for SACHRP approval 11 that the definition of minimal risk when applied to 12 Subpart D should be interpreted as those risks 13 encountered by the normal average healthy children 14 living in safe environments. 15 Now, what do we mean by "normal average 16 healthy"? We mean children whose lives ordinarily 17 involved greater risk, like children who are taking 18 toxic drugs to treat cancer or children who live in 19 violence-prone neighborhoods should not be subjected 20 to greater research risk than other children under the 21 umbrella of minimal risk. Remember, they're still 406 22 and 407. 29 1 Similarly, children living in safe 2 environments means children living in unsafe 3 environments, like those who are exposed to violence 4 or those who are exposed to high levels of lead or 5 other environmental toxins should not under the 6 umbrella of minimal risk be exposed to those toxins 7 when children living in safer environments would not 8 be. And so we attempted to include lots of 9 references, even though some of them may be redundant, 10 just to be clear on what is being meant. 11 Now, it's not enough simply to give those 12 examples of normal average healthy safe environment. 13 It's also important that minimal risk be age-indexed, 14 meaning that you are not going to subject an infant to 15 what are the daily life risks of an adolescent. And, 16 similarly, so as one goes up the developmental ages, 17 it has to be indexed to what is in the daily life and 18 what is in the routine medical and psychological 19 experiences of the child. 20 Now, there are limitations. One of the 21 things that we wanted to do at the last meeting was to 22 discuss what are the continuing problems with what we 30 1 presented to you last time. And so we attempted to 2 try to see whether or not our recommendations were 3 adequately addressing the limitations of daily life 4 and routine examination indexing. And the risks are, 5 the problems are that risks could be over or 6 underestimated. 7 So, for example, we need to keep in mind 8 that there are certain IRB approval decisions that are 9 limited to only minimal risk research with children. 10 That is, you can only do expedited review if it's 11 minimal risk. You can only waive parental permission 12 if it is minimal risk. 13 And if, in fact, you want to do 14 non-beneficial research with the normal healthy 15 average child living in safe environments, you can 16 only do it if it is minimal risk. You cannot do any 17 minor increment over minimal risk unless the child has 18 a disorder or condition, as defined by 406. 19 So the potential limitation of all of 20 these is that it may exclude good research; that is, 21 actually minimal risk with normal average healthy 22 children or with kids with a disorder. It might 31 1 prevent the expedited review. It might prevent an 2 appropriate waiver of parental permission or, at the 3 same time, it might expose kids. It might allow 4 expedited or waiver when the risk is really higher. 5 So to give an example, this is an example 6 where there might be an underestimation of risk. 7 Exposure to small puffs of smoke -- anybody who walks 8 around may pass somebody smoking -- may be minimal 9 risk for healthy children but greater than minimal 10 risk for severely asthmatic children. 11 So does the definition of daily risk mean 12 the children who are vulnerable and to the risks 13 greater than those of the normal average child could 14 be subjected to those risks under experimental 15 procedures? 16 And so here we have our proposal which we 17 gave you last time. The uniform, age-indexed 18 definition of minimal risk should represent the upper, 19 not the lower, limits of risk to which children can be 20 exposed. That is, the IRB has to take into 21 consideration that there are some children for whom 22 the risks of daily life for normal average healthy 32 1 children are greater for them because of physical, 2 medical, environmental, or psychological reasons. 3 So this would seem quite obvious, but we 4 are trying to include if SACHRP and OHRP want to 5 accept these guidelines education for the IRB so that 6 they are continuing to deliberate in a way that is 7 protective of children and also permits the conduct of 8 good and important minimal risk research. 9 Case two is dextroamphetamine. Here is an 10 example of a possible overestimation of risk that may 11 prevent minimal risk research from occurring. The 12 goal of this hypothetical study is to understand and 13 compare ADHD children's brain reactions to those of 14 normal children when exposed to dextroamphetamine. 15 The procedure requires a very small dose 16 of dex for children with and without ADHD for purposes 17 of imaging the effect on the brain. The probability 18 and magnitude of harm in and of itself not indexing to 19 daily life or routine procedures are very, very small, 20 but administration of dex is not part of the normal 21 child's daily life nor well child visit, although one 22 might equate it to drinking a lot of caffeinated sodas 33 1 or cough medicines. 2 And although the magnitude and probability 3 of harm are very low, an IRB might be forced to use 4 406; that is, minor increment over minimal risk, to 5 push the kids with ADHD into an acceptable standard or 6 regulation. 7 At the same time, they could not push the 8 normal children into that because the normal children 9 don't have a disorder or condition. And so they might 10 then have felt coerced into or forced into if they 11 thought the study was important, appropriate, and safe 12 to either push this into a 407 review or in some cases 13 to say that there is some probability of benefit, 14 which would be to push it into a 405. 15 I think our concern has been and the 16 concern of I think OHRP and others, when do our 17 regulations push IRBs and investigators into 18 attempting to craft other regs into a research study 19 to which it is inappropriate. This is a problem we 20 are finding as we continue to move throughout all of 21 the regs. 22 Okay. So that is where we come into the 34 1 recommendation of equivalent procedures. When we are 2 talking about minimal risk and that it is indexed to 3 the daily life or routine procedures for healthy 4 average normal children living in safe environments, 5 we are not talking about the exact instances of their 6 life or the exact procedures that are used in these 7 well child visits but, rather, equivalent in magnitude 8 and probability of risk. Okay? 9 So proposal five is saying IRBs look to 10 whether or not it's equivalent, not to whether or not 11 these kids actually have that experience themselves 12 but is it equivalent to the experiences that they do 13 have. 14 And I am going to move on a little bit in 15 terms of what we mean by equivalent, but I did want to 16 remind SACHRP and everyone here because we use this in 17 our subcommittee that 46.11.2 in evaluating the 18 magnitude of harm and probability of risks, IRBs 19 should consider only those risks that may result from 20 the research itself. 21 So there may be instances where children 22 are undergoing medical procedures or they're in 35 1 procedures to which there is a 405, an intervention 2 component. But we're talking about, then, whether or 3 not we want to take on something for non-direct 4 benefit purposes but that will provide us knowledge, 5 so just to keep that in mind as you think of examples. 6 Okay. Back to the equivalence criteria. 7 So, remember, we are recommending that IRBs use an 8 equivalence criteria. And we're saying that 9 equivalence means are the probability and magnitude of 10 harm in the research procedures themselves that are 11 non-beneficial equivalent in duration, equivalent in 12 cumulative characteristics, and equivalent in 13 reversibility of harm to the risks of daily life or 14 routine examinations? 15 And here we tried to define what is meant 16 by duration, cumulative, and reversibility. Duration 17 is the length of time the child will be involved in 18 the experimental procedure. Is that similar to the 19 length of time they would be involved in whatever 20 procedure is the equivalent in the well child or other 21 type of routine examination or their daily life? 22 Cumulative. Is the magnitude of the harm 36 1 and the probability of risk on a cumulative level the 2 same? That is, if you are giving repeated 3 venipunctures, it may be that venipuncture in and of 4 itself could be minimal risk, but if it's repeated 5 over time, that would be a cumulative effect. 6 Reversibility. What do we mean by that? 7 And this is interesting. Reversibility, it may be 8 that the procedure itself is reversible. That is, if 9 you get a blood test, the prick may hurt for a very 10 short duration and have no cumulative effect and heal 11 by itself. 12 That is one kind of reversible effect. 13 But the other kind of reversible effect to remember is 14 the investigator's actions can mediate or moderate the 15 effects. 16 So, for example, if there is a risk that 17 a child might feel faint after a blood draw, if the 18 investigator is going to provide juice or a place to 19 lie down, that can create an equivalence to a minimal 20 risk situation. 21 If there is a concern that some children 22 may be anxious having an MRI, which the MRI itself may 37 1 be of minimal risk but the anxiety may be considered 2 by some IRBs a minor increment over if, in fact, there 3 is going to be relaxation and peer counseling or 4 whatever is appropriate to allay the initial anxiety 5 and to remediate any anxiety that is going on, the 6 child is withdrawn, et cetera, et cetera, then, once 7 again, that could be considered minimal risk. 8 Okay. Proposal 7 is when you're indexing 9 to routine medical or psychological examinations, what 10 is meant by that. Well, going with the IOM 11 conclusions, there really is no definition of a 12 routine medical examination. However, what might be 13 most equivalent is a well child visit. And, remember, 14 these are indexed to age as well. 15 So here is a list from IOM of those kinds 16 of experiences that a child would have in well child 17 visit. And I am not going to go over all of them. 18 You can refer to them. 19 Now, in addition to a well child visit 20 being a reference for routine medical examinations or 21 tests, it can also be a referent for routine 22 psychological examinations. For example, in a well 38 1 child visit, physicians will typically attempt to 2 identify potential health risks relevant to the family 3 medical history. 4 So, for example, when you look at this, think 5 about the types of questions that might be asked on a 6 social, behavioral survey and the extent to which IRBs 7 could say, "Wait a minute. Are those the kind of 8 things that I don't have to imagine myself whether or 9 not they're above minimal risk but I can think about 10 whether or not these are the kinds of questions kids 11 are typically asked and families are asked in routine 12 visits, health risks, family medical history, lack of 13 seat belt use; for adolescents, exploration of sexual, 14 smoking, illicit drug use, and other 15 health-compromising behaviors, relevant family 16 health/behavioral history." 17 Now, of course, I am not talking about 18 confidentiality issues, which, once again, when you 19 are looking at minimal risk, one has to look at 20 whether or not the investigator has put in the 21 adequate confidentiality protections. 22 The next thing we are proposing to help 39 1 IRBs and to ground in some kind of consensus what is 2 meant by a routine psychological examination or test 3 is that there are many screening and assessment 4 measures out there that are used by social, 5 behavioral, and clinicians and they measure these 6 types of things. 7 You know, we could provide lists of the 8 tests themselves, but these are the examples of the 9 types of things: intelligence tests, tests about 10 social development, neurological or motor disorders, 11 emotional regulations, feelings of sadness or 12 hopelessness. 13 Now, these are typically measures that are 14 given either to children who have not been referred or 15 children who have been referred but for whom there is 16 not a diagnosis as of yet. And so they're not 17 in-depth. They're basically screening and assessments 18 for children who may or may not have a problem. 19 Now, what are the possible exceptions to 20 routine psychological tests as minimal risks? IRBs 21 worry about, well, if you ask somebody about suicide, 22 if you ask them about child abuse, is that greater 40 1 than minimal risk? So we attempted to address that 2 concern. 3 Now, actually, as I was going over this, 4 I realized that proposal 4 addresses this in the sense 5 that, remember, we said that the uniform, age-indexed 6 definition of minimal risk should represent the upper, 7 not the lower, limits of risk. So that IRBs always 8 have the right to say, "Wait a minute. Is there a 9 special population that may be at greater risk?" 10 The nice thing about this is that it's 11 trying to say, "Well, is the normal average healthy 12 child at risk for a question about suicide or a 13 question about drug use or a question about sexual 14 behavior or trauma?" But who is the population that 15 the research is testing? 16 One of the important things is that 17 epidemiological survey research if it is not permitted 18 under a minimal risk to ask these kinds of questions 19 would be very problematic. We would not get 20 population information. And so we need to think about 21 not over or underestimating the risk. 22 So proposal 10 as I look at it now is 41 1 really a more specific guidance on proposal 4 and 2 whatever the other number proposal is for equivalence 3 because this is guiding IRBs to say, "How do you think 4 about whether or not there is greater risk involved in 5 some of these questions?" 6 First of all, is the duration of the 7 psychological testing that is going to be going on 8 greater than what is usually experienced in standard 9 psychological tests? That, of course, has to be 10 age-indexed, one to three hours depending on the 11 child's day. However, if, in fact, you do have a 12 large battery, if you test across one or two days, 13 then the duration may be equivalence. 14 Is there evidence that there are going to 15 be persistent post-experimental reactions? Now, here 16 the evidence is important. Is there an established 17 body of evidence that suggests that the population 18 that is going to be involved in the research is 19 subject to harm, to post-experimental stress following 20 the study? 21 And so trying to ground IRBs in whether or 22 not there is evidence and not whether or not they are 42 1 simply very anxious and don't know -- and, of course, 2 I have always thought that it is the responsibility of 3 the investigator to educate the IRBs. It is not the 4 responsibility of the IRBs to go out and do a lit 5 search to see whether or not there is or is not 6 evidence, but it's the responsibility of the 7 investigator to say there is or is not evidence of 8 whether or not there are post-experimental reactions 9 and then, once again, in terms of investigator 10 reversibility, whether or not there are plans to 11 identify follow-up and remediate if the negative 12 reactions occur. And so that is a way of seeing 13 whether or not research which is in these sensitive 14 areas is or is not of minimal risk level. 15 Okay. Now, the next proposal has to do 16 with the daily life criteria. Are we saying that 17 anything that is done in daily life is fine in terms 18 of being a referent for experimental procedures and 19 based on the IOM and our own discussions that there is 20 a difference between some risks that are permitted in 21 society because they are viewed as appropriate 22 socialization activities or can enhance growth 43 1 development that would not be appropriate for 2 research? 3 Example given is kids play football. It 4 can be very dangerous. However, within the context of 5 sports, social development, and all of those physical 6 developments, it is considered in society to be an 7 appropriate balance. However, asking a child to hit 8 their head against the wall or risk dislocating their 9 arm in a research procedure should not be considered 10 minimal risk. It sounds obvious. 11 Okay. So here we have possible exceptions 12 to the daily life equivalence. Some risks in the 13 daily lives of normal healthy average children may not 14 be minimal in probability and magnitude of harm. Such 15 risks may be socially acceptable because the 16 activities are associated with, as I said, benefits to 17 the child in his or her actual life, but these same 18 risks are not acceptable as minimal risks but 19 introduced solely for the purpose of non-beneficial 20 research. 21 Okay. Now, we're almost to the end of 22 minimal risk. And how did this apply to international 44 1 research? This is a very interesting question. Why 2 are we bringing this up? Well, the issue of uniform 3 versus relative is a highly important issue in 4 international research. 5 So there is an increasing number, as you 6 are well-aware and we have heard at SACHRP. A number 7 of studies occur outside the U.S., where the 8 probability and magnitude of harms associated with 9 risk in the daily life of children are much greater 10 than they are in the United States. 11 And so the question we had to deliberate 12 on was whether or not we should apply the uniform 13 standard uniformly in the United States and 14 internationally when research comes under federal 15 regulations. And our conclusion was that yes, all of 16 the ethical rationales, justice, beneficence, 17 non-maleficence, we can't stand them on their head and 18 say they don't count when we are using federal 19 regulations to study children abroad. And so if we 20 are using a uniform definition, that rationale has to 21 stand. So our recommendation is that the uniform 22 standard must apply internationally to minimal risk. 45 1 Now, remember, both in the United States 2 and internationally, the minimal risk criteria does 3 not prevent investigators from studying greater than 4 minimal risk when it occurs naturally in a child's 5 environment. What we are talking about is adding the 6 risk, is that the experimental procedure presents the 7 risk. 8 So that, for example, in our country or in 9 another country, if a child is -- well, it might not 10 apply because of laws in our country, but if a child 11 is prostituting in another country, clearly we would 12 never have an experimental intervention that would 13 permit that. However, we might do ethnographic 14 research in that area with asking children about their 15 experiences. 16 So just keep in mind that we are saying 17 that non-beneficial research; that is, acquiring 18 knowledge that is very important to children who are 19 living in risk circumstances, cannot be conducted 20 internationally but that those of us under federal 21 regs cannot expose those children under the minimal 22 risk umbrella to greater risk than we would do under 46 1 the minimal risk umbrella in this country. 2 Okay. So here is a summary. And I think, 3 Ernie, if you think it is appropriate, should we stop 4 here and try to see if there are some decisions and 5 comments about all of these? 6 CHAIRPERSON PRENTICE: Sure. Okay. 7 Thanks, Celia. And thanks to your subcommittee. You 8 have done a very, very comprehensive job here. I 9 think that is quite evident by your presentation. 10 Asserting chairman's prerogative, I will 11 ask a couple of questions. And then I will ask 12 everyone else to signify by raising your hand that you 13 want to ask a question. We will try to keep this as 14 orderly as possible. 15 You have a slide pertaining to living in 16 safe environments. This is perhaps more semantics 17 than anything else, but you are talking about exposure 18 to unhealthy levels of lead. "But such risks are 19 neither socially desirable nor ethical when introduced 20 through experimental procedures defined as minimal 21 risk." That suggests that it is ethical to expose 22 kids to lead in a non-research context, but it's not 47 1 in a research context. 2 I would suggest after "ethical," inserting 3 a comma and then saying, "particularly." Do you see 4 where I am going in that? That's page 8, page 8, the 5 first slide, "But such risks are neither socially 6 desirable nor ethical, particularly when introduced 7 through experimental procedures defined as minimal 8 risk." 9 MEMBER FISHER: Oh, yes. 10 CHAIRPERSON PRENTICE: Do you see where I 11 am going on that? 12 MEMBER FISHER: Yes. 13 CHAIRPERSON PRENTICE: I mean, that is a 14 subtle point, but I think it is important because we 15 are not endorsing those conditions. 16 MEMBER FISHER: Right, right. That is 17 good. 18 CHAIRPERSON PRENTICE: All right. On page 19 13, the proposal 6 and also on page 19, proposal 12, 20 you -- no. That was not 19. It was 18, rather, 21 proposal number 11. You keep on referencing minimal 22 risk to its application to non-beneficial research. 48 1 That kind of confused me because basically minimal 2 risk applies to research, period, whether it is 3 beneficial or hot beneficial. 4 I mean, when you say, "404," it's research 5 not involving more than minimal risk. That does not 6 imply that there is no benefit to that research. You 7 could have interventions. 8 Do you see what I am saying? 9 MEMBER FISHER: Yes. 10 CHAIRPERSON PRENTICE: So I think you have 11 made that reference in one comment. And then it was 12 also on a slide. 13 MEMBER FISHER: Yes. 14 CHAIRPERSON PRENTICE: And I think that 15 could be misleading. 16 MEMBER FISHER: Right. 17 CHAIRPERSON PRENTICE: Do you agree? 18 MEMBER FISHER: Right. 19 CHAIRPERSON PRENTICE: Okay. My last 20 question pertains to page 19, proposal number 12. 21 That is the uniform standard must apply 22 internationally. I certainly agree with that. 49 1 However, -- and correct me if I am wrong, OHRP -- it 2 is my understanding that OHRP accepts equivalent 3 standards. And equivalent standards don't necessarily 4 have Subpart D in them. Is that not correct? Mike? 5 Melody? 6 DR. CAROME: Under the FWA, Subparts B 7 through D would apply. 8 CHAIRPERSON PRENTICE: Would apply? 9 DR. CAROME: Yes. 10 CHAIRPERSON PRENTICE: Okay. Period? So 11 you have to comply with that? 12 DR. CAROME: Yes. 13 CHAIRPERSON PRENTICE: Okay. And you have 14 to have an assurance at an overseas site that they say 15 they will comply with Subpart D. All right. 16 Then one extension of that question, -- 17 and I guess this is for David LePay -- is FDA looking 18 at Subpart D in any way independently from SACHRP? 19 DR. LePAY: No. I think that we are very 20 much following the deliberations that are going on 21 here as well as, of course, we have been quite 22 well-connected with the Institute of Medicine study 50 1 and its report. 2 CHAIRPERSON PRENTICE: Okay. Then I guess 3 a further question, FDA endorses the ICH guidelines as 4 providing equivalent standards when you are going to 5 import data from overseas. How does that relate to 6 complying with Subpart D? 7 DR. LePAY: The Subpart D requirement for 8 FDA regulations pertains to research that is conducted 9 under an IND or an IDE that is under FDA regulations. 10 What you are citing here are standards for the 11 acceptance of non-U.S., non-IND data; that is, data 12 that is generated and then brought to FDA after the 13 studies are completed. 14 The criteria, again, in the good clinical 15 practice guidances, such as ICH, are becoming the 16 standard for what we are basing our acceptance on. 17 There is a proposed rule out now for public comment. 18 I should say the public comment period just closed. 19 So I am not sure I am precisely answering 20 your question. The answer to your question is for 21 most non-U.S. research, it is submitted to FDA outside 22 of the IND process. And, therefore, it falls into a 51 1 separate set of regulations bed largely on ICH or 2 world-accepted standards for good clinical practice 3 conduct that are separate from FDA's regulations. 4 CHAIRPERSON PRENTICE: Okay. Thanks. All 5 right. The floor is open. Felix, are you getting 6 ready to say something? 7 MEMBER GYI: Just a point of clarification 8 because I am not sure if I heard you correctly. When 9 you said that international research and the 10 regulations and the recommendations that we are making 11 should apply to international research but if in the 12 course of normal living a child is exposed to duress, 13 a child is out in the wilds of Africa and is exposed 14 to the wilds of the environment there, how is that 15 different from the type of research that the 16 Kennedy-Kreiger Institute undertook with the lead 17 abatement? I am trying to just understand how we 18 balance what is normal risk in activities of daily 19 living. 20 MEMBER KORNETSKY: I think what we are 21 trying to do is to remove that, sort of to remove that 22 issue. You know, you could say that children living 52 1 in ghettos are exposed to violence all the time. We 2 are trying to remove that. Therefore, they can be 3 exposed to more risk. 4 So if you were out in the wilds of Africa, 5 you wouldn't want to take that into consideration and 6 say, "Well, these kids can be exposed to more risk 7 because they are exposed to a lot more diseases or 8 whatever." 9 I am not sure why you are sort of bringing 10 that sort of an international context. I think we are 11 trying to, wherever kids are exposed to more risk, 12 sort of put all children on a level playing field. 13 MEMBER BARNES: I can try to answer that 14 perhaps and give you a rationale, but the rationale 15 actually doesn't matter between whether it is 16 international research or whether it's domestic-based 17 research. 18 The issue, the conclusion here is somewhat 19 perverse, frankly, but basically what Susan and Celia 20 said is right. We would never subject kids willingly 21 or anyone to prostitution as a method of earning money 22 or as a lifestyle, but we would and do find merit in 53 1 studying why it happens and how risks can be better 2 controlled and people can be protected and kids can be 3 protected. 4 I think it is different than the way the 5 Supreme Court of Maryland saw it in the 6 Kennedy-Kreiger case because in the Kennedy-Kreiger 7 case, there actually was an intervention that was 8 given for three different classes of individual 9 children whose families were enrolled in the study. 10 Basically, the research design was such, 11 as I understand it, as least as reported in the 12 decision, the research design was such that the 13 researchers made available and implemented different 14 levels of protection or different levels of 15 intervention for lead abatement for the three 16 different categories of families, depending on which 17 arm of the study they were enrolled into. 18 So instead of simply studying children in 19 their environment without any intervention, in fact, 20 there was intervention that was given by the 21 researchers as part of the study design. 22 Now, what is perverse about that is that, 54 1 in fact, one could say in sort of an overall social 2 justice perspective that I think this is what the 3 researchers in that study, that this was their -- I 4 don't want to put words in their mouth, but as I 5 understand it, this was their ethical or moral 6 position, that they were at least giving interventions 7 to make things better for all the children than what 8 the children had to begin with, but they were faulted 9 for not giving the best available intervention to 10 those children. And that actually has been the middle 11 ground that has been debated and that makes the 12 Kennedy-Kreiger so interesting and also so perplexing. 13 Does that help? 14 MEMBER FISHER: Let me say something else. 15 I think what Mark was saying and your question were 16 getting to what I think will be our next steps. Are 17 the minimal and minor increment definitions pushing 18 people into saying that something is a 405? Because, 19 in other words, we also -- and I think that is going 20 to be our next thing that we need to look about, phase 21 I trials and housing hazard types of research and the 22 extent to which if it's below standard for the normal 55 1 average healthy child but above standard for a child 2 who doesn't live in a safe environment or a child who 3 has cancer or something like that, can we call it an 4 intervention, a beneficial intervention, when we would 5 never give that intervention to a kid with a better 6 environment? 7 I would also say that one of the problems 8 with always referring to the Kennedy-Kreiger is that 9 my experience has been it's a Rorschach test. I mean, 10 nobody seems to really know what actually went on 11 there and whether it was an intervention or not an 12 intervention. My understanding is they didn't approve 13 it under a 405. Right? 14 So I think what is very helpful is that 15 whenever we talk about Kennedy-Kreiger, which is a 16 wonderful thing to reference to, we say exactly what 17 we think Kennedy-Kreiger is. And whether or not we 18 are right or not, at least we all know we are talking 19 about the same thing. An that's addressed to myself 20 as well. 21 So in that example, I would say that there 22 is a difference between going into a child's home and 56 1 measuring lead and they already live there. Okay? 2 That's not an intervention that is the experimental 3 part. What would be the experimental part were the 4 procedures used to study the lead levels in the 5 childhood lead levels in the home. An experimental 6 act would be to randomize kids into varying levels. 7 And so it would be okay in international 8 research to observe, measure, assess. Let's say kids 9 are being exposed to some kind of disease and you want 10 to do blood tests to see how many kids have it in 11 their blood or whatever it is. The only experimental 12 procedure there is the blood test, but you are not 13 exposing the kids to the disease. 14 So I think it is important that we all 15 make those distinctions when we are trying to say -- 16 and so minimal risk is trying to say, what are we 17 permitted to do that is introduced solely because this 18 is research? And what should be the gateway limit for 19 all children in terms of what we are allowed to do 20 experimentally, whether or not it is intervention or 21 non-intervention? 22 MEMBER WEINER: I actually have a point of 57 1 clarification and a question about the contrast 2 between exceptions to routine psychological tests and 3 the lack of exceptions of routine medical procedures. 4 I am kind of worried about the unintended 5 consequences of doing that because in some sense, 6 routine medical procedures are likely to change 7 radically over the next few years. 8 And Lord knows I don't want to further 9 constrain the definition of minimal risk, but we 10 haven't applied the same standards of reversibility 11 and duration on page 17 in proposal 10 to the well 12 child visit, to the procedures in the well child 13 visit. And that asymmetry is troubling to me because 14 I am not sure what its ripple effects would be. 15 MEMBER FISHER: You know, that began to 16 trouble me, as I mentioned. But what I realized was 17 we actually do -- and I don't think we need a separate 18 10 per se because if we look at -- I think we need to 19 look and see if this is correct, but if we look at 20 proposal 4, the upper limits of risk and harm, that 21 IRB still must consider whether or not a child is more 22 vulnerable to an average risk, then you look at 5, 58 1 which says, "It has to be equivalent procedures." 2 But then you look at 6, which is duration 3 -- I absolutely agree it takes away from this. And I 4 think this has -- and I agree with you. 5 MEMBER HAUSER: Question about parental 6 permission. My understanding is that in minimal risk 7 research, parental permission is waived. Is that -- 8 MEMBER FISHER: It can be. 9 MEMBER HAUSER: It can be waived. It 10 doesn't have to be waived. So it would be the 11 judgment of the IRB as to whether or not that would be 12 waived? 13 MEMBER FISHER: Yes. 14 MEMBER HAUSER: Thanks. 15 MEMBER KORNETSKY: I just also wanted to 16 clarify there are other criteria for waiving it. And 17 there are also other provisions within the children's 18 regulations when it wouldn't be feasible. 19 So the minimal risk route is one route. 20 And then there is another route for waiver of parental 21 permission as well. The IRB needs to deliberate and 22 talk about those things. 59 1 MEMBER HAUSER: So there is guidance for 2 the IRBs as to when and when not it would be waived? 3 MEMBER KORNETSKY: There are regulations, 4 and there are in 408. I think it is an area that 5 there is still a lot of controversy about it, maybe 6 something that our subcommittee can look at at some 7 point, but yes. 8 MEMBER GYI: Celia, if we drop proposal 9 10, it mentioned, at least in that proposal, that 10 persistent post-experimental reactions be provided, 11 that information be provided to the IRB by the 12 investigator. I still think that that is an important 13 element that needs to be considered by the IRB. 14 If we drop that proposal, will that be 15 incorporated elsewhere? 16 MEMBER FISHER: When we look at the 17 definition of reversibility, there are two questions. 18 One is investigator actions should be able to be -- if 19 there is some evidence that there might be some 20 post-experimental reactions or the IRB is concerned 21 but doesn't know, then I think it is important that 22 investigator actions, IRBs understand that 60 1 investigator actions, can keep a concern at a minimal 2 risk level if they're going to do the right things. 3 Now, I think your question is -- that's in 4 condition. We don't have that anywhere else. Right. 5 So you're asking the evidence, and you are interested 6 in the fact that investigators need to provide 7 evidence that there is no risk or there is risk. 8 I think we should discuss that because I 9 think it is important to do, but I am also very much 10 aware of the burden because for most of these things 11 -- actually, I have been doing a lit search -- for 12 most experimental procedures or even for questions 13 being asked to adolescents, there is no literature. 14 So I think that putting in some kind of a 15 guidance that says investigators must provide evidence 16 I think would be problematic because in most cases, 17 there is no evidence. 18 So the question is I think it's important 19 that investigators do this. Whether or not it should 20 fit into OHRP guidance is a question for me. 21 MEMBER KORNETSKY: Yes. I don't see that 22 any differently than anything else the IRB reviews 61 1 when they get into risk-benefit determinations, that 2 the investigator needs to educate the IRB and provide 3 information on anything to do with risks and benefits. 4 I'm not sure that's where you want, what 5 the issue is. 6 MEMBER GYI: Where I am going with that is 7 to alleviate the IRB of the burden of having to come 8 up with the information. If we remain silent on this 9 and because you have addressed this here from the 10 perspective of having the investigator be responsible, 11 at least have them have some ownership on that and not 12 put the ownership on the side of the IRB. 13 MEMBER FISHER: I agree with Susan, and 14 maybe Ernie or Mike has a comment on this or Dr. 15 Schwetz. I think investigators are always 16 responsible. And IRBs can say, you know, "We are 17 concerned about this risk. What do you or do you not 18 know about it?" 19 It's just hard to make that a reg or 20 guidance because investigators should do that anyway. 21 They are submitting a proposal. And if it is adequate 22 in terms of the type of information that they 62 1 provided, then the IRB is going to tell them that. 2 So I am just not sure phrasing it in a 3 very specific sense may be more harm than good because 4 requiring investigators to provide data on risk may 5 not be possible in most instances. 6 And what risk is, I mean, we were just at 7 an IOM public meeting, in which some people suggested 8 risk is actuarial. Others suggested risk was the 9 perception of those will be exposed to the risk. 10 So I am not sure we even know whether or 11 not it would be easy in federal regulations to do that 12 kind of criteria. 13 CHAIRPERSON PRENTICE: Thank you. Celia 14 and Susan, let me ask you a question with regard to 15 your uniform versus relative risk statement. I begin 16 with page 4, the preamble, the '81 preamble, which 17 indicated that the framers of the regulations were 18 thinking of utilizing the relative standard of minimal 19 risk aside from the daily lives of the subjects of the 20 research. Okay? 21 Then we go to page 3. And it's uniform 22 versus relative risk. If you look at the definition 63 1 of a relative standard, the type of risk to which 2 particular children involved in experimentation are 3 typically exposed, I don't really think it's 4 experimentation. Right? Do you agree? 5 MEMBER KORNETSKY: Yes. 6 CHAIRPERSON PRENTICE: Page 14, 7 reversibility. I certainly think that reversibility 8 is a criteria for establishing whether or not a 9 procedure is minimal risk or not. 10 And I look at your examples. I am looking 11 at, for example, the MRI. It is very clear that an 12 MRI depending upon the age of the child and what the 13 investigator does or not do can be reasonably 14 classified as minimal risk or not minimal risk. 15 I am wondering how an IRB would get at 16 what is done here. If you are, for example, a 17 radiologist that does MRIs for a living, particularly 18 one who works at a children's hospital, the IRB could 19 almost assume that that individual would do everything 20 right. 21 Are you suggesting that in order to 22 establish reversibility IRBs should be asking 64 1 investigators what they are going to do? 2 MEMBER KORNETSKY: I would answer that 3 yes. 4 CHAIRPERSON PRENTICE: You would? 5 MEMBER KORNETSKY: Yes. 6 CHAIRPERSON PRENTICE: And you work at a 7 children's hospital. So if you were to ask your 8 radiologists -- 9 MEMBER KORNETSKY: We would not assume 10 that an MRI in a young child is minimal risk. We 11 would want to know what they are going to do. Are 12 they going to bring the kid to the MRI machine first? 13 Are they going to show him a video? Are they going to 14 bring him in for an hour so that they can sit and 15 play? Yes, we would ask that. 16 CHAIRPERSON PRENTICE: How about the 17 drawing blood? Are you going to ask them if they are 18 going to give the kid juice? 19 MEMBER KORNETSKY: Well, I am not sure 20 this is a great example because I think in general 21 drawing blood except in a certain age group probably 22 is minimal risk. So I am not sure that that one is a 65 1 great example to include. 2 CHAIRPERSON PRENTICE: Okay. Thanks. 3 MEMBER HAUSER: But it does illustrate a 4 point. And that is for an MRI in a child, you are 5 likely to need sedation. That is another thing. 6 CHAIRPERSON PRENTICE: Okay. 7 MEMBER WEINER: That is part of the whole 8 procedure; that is, the sedation, plus the MRI. It's 9 the research procedure. 10 MEMBER FISHER: But would sedation ever be 11 considered minimal risk? No. 12 MEMBER KORNETSKY: There are a lot of MRIs 13 in our hospital done on kids of lots of ages without 14 sedation. They hook them up to music and other types 15 of things. 16 You are right. In some kids, you might, 17 and that may bump it a category. But I don't think 18 you do all. Adults need sedation more than kids 19 sometimes in the MRI. 20 CHAIRPERSON PRENTICE: All right. Celia, 21 how would you like to proceed? 22 MEMBER FISHER: I would like to maybe just 66 1 go over each of the proposals quickly and just see 2 where there is contingent agreement, as we had for the 3 uniform because, as I said, in order to go to anything 4 else, we need to see whether this in principle works. 5 I think, once again, it is a contingent 6 approval, but we need to see where there is strong 7 feeling that if nothing surprising comes up, this is 8 where we would want to go in minimal risk. 9 MEMBER WEINER: Do you mean contingent or 10 do you mean conditional? In other words, what is it 11 contingent on? 12 MEMBER FISHER: Well, I guess it is 13 contingent on everything: the minor, the 405. So 14 whether you say conditional or contingent, I don't 15 care. The -- 16 MEMBER WEINER: So it is temporary until 17 something else happens. In other words, we are 18 approving this chunk of work on the assumption that 19 the entire thing will have an independent affirmation. 20 CHAIRPERSON PRENTICE: You are reserving 21 the right to come back and look at everything. 22 MEMBER WEINER: Right. 67 1 MEMBER KORNETSKY: I think the thing that 2 is helpful is to go back to the subcommittee and say 3 there weren't any questions or issues. We can sort of 4 accept this and move on. But obviously when 5 everything is done, this will have to come back as a 6 full package and everyone vote on it before it goes to 7 the Secretary. 8 CHAIRPERSON PRENTICE: Okay. Let's go to 9 the proposals. And I am not going to ask for a motion 10 on each one. We'll ask for discussion. If you have 11 any concerns, you voice them. 12 Proposal 1, the uniform standard, we 13 conditionally approved this recommendation at our July 14 meeting. Are there any concerns now about proposal 1? 15 (No response.) 16 CHAIRPERSON PRENTICE: Proposal 2, this is 17 now a reference point for the uniform definition. Any 18 concerns? Any discussion about proposal 2? 19 (No response.) 20 CHAIRPERSON PRENTICE: Proposal 3, minimal 21 risk should be age-indexed. Any problems with 22 proposal 3? 68 1 (No response.) 2 CHAIRPERSON PRENTICE: Proposal 4. There 3 is now an upper limit of risks and harms. Any 4 problems? 5 (No response.) 6 CHAIRPERSON PRENTICE: Proposal 5, 7 equivalency. Any problems? 8 (No response.) 9 CHAIRPERSON PRENTICE: Proposal 6, the 10 criteria for equivalency. Any concerns or problems? 11 (No response.) 12 CHAIRPERSON PRENTICE: You've done a good 13 job, guys. Proposal 7, the well child visit 14 reference, which is tied to routine medical 15 examinations or tests that would be a part of a well 16 child visit. Any problems? 17 MEMBER BARNES: I do have just one 18 suggested wording change for that. Instead of saying 19 that "the routine medical exam offers a reasonable 20 basis," could we say "offers one reasonable basis" 21 because there are many other bases? This is one of 22 many reasonable bases. 69 1 CHAIRPERSON PRENTICE: Anybody have any 2 objections to that modification? 3 (No response.) 4 CHAIRPERSON PRENTICE: Proposal 8, well 5 child visit, the reference for routine psychological 6 examinations or tests. Any concerns or problems with 7 proposal 8? 8 (No response.) 9 CHAIRPERSON PRENTICE: Proposal 9, this is 10 the index for the routine psychological tests. It's 11 standardized screening or assessment measures, and 12 they're all listed. Any problems with the list? 13 Proposal 10. I'm sorry? What? 14 MEMBER BARNES: I do want to ask something 15 about this. This is not an exclusive list. And I 16 would just like to point that out as a friendly 17 amendment. 18 MEMBER WEINER: Do we want to include 19 educational as well as psychological in that? 20 MEMBER FISHER: The reason it is not in 21 the proposal is because of the language, right? It's 22 only psychological, but we will put it in the list. 70 1 CHAIRPERSON PRENTICE: You are deleting 2 11? 3 MEMBER GYI: Before we get there, can I 4 just ask another question? I don't want to stay with 5 this. If everybody has a really good understanding of 6 this, I will let this go, but I would like to raise 7 this one more time. 8 There was some wisdom to the subcommittee 9 raising the issue or asking the question, is there an 10 established body of evidence to suggest that there 11 will not be persistent post-experimental reactions and 12 understanding that this is in the context of a 13 psychological test and defining minimal risk and 14 appreciating if that is where we want to focus our 15 efforts and help the IRBs. 16 This particular statement says to me that 17 the investigator is at least asked the question, help 18 the IRB understand that there is some knowledge or 19 there isn't some knowledge. In the absence of 20 guidance in this area, then the IRB is held 21 responsible for doing some kind of a literature search 22 or establishing minimal risks. 71 1 My concern is that in today's environment, 2 where there are lots of shifts of burden, in the 3 absence of a statement like this in the guidance 4 somewhere, the IRB will be saddled with having to 5 establish that kind of a risk assessment. 6 MEMBER FISHER: I think Susan and I are 7 looking at that. And maybe we could imbed it 8 somewhere into proposal 6 and in the slides that 9 follow in terms of what we're talking about. 10 I think your point is well-made, not just 11 to lift the burden from IRBs but also to lift the 12 burden from investigators that when an IRB says, 13 "Well, I believe this is going to be risky," the 14 investigator can also say, "But wait a minute, you 15 know the evidence is it's not" or whatever. 16 So I think it's a very good guidance for 17 procedures in general to attempt, where feasible, 18 ground risk estimates in some kind of evidence. 19 MEMBER KORNETSKY: The other place, 20 though, that we may be able to do it is in accepting 21 a uniform standard. We may be able to either -- when 22 this is written up as guidance, I can easily sort of 72 1 -- these are little bullet points now, but saying that 2 when we're talking about these types of uniform 3 standards, that that has to be based on some type of 4 evidence that way. 5 I think we don't have to lose the point, 6 Felix. I think we can put it someplace in here. 7 MEMBER FISHER: We will. 8 CHAIRPERSON PRENTICE: All right. Ten. 9 MEMBER FISHER: Ten is out. 10 CHAIRPERSON PRENTICE: Out? 11 MEMBER FISHER: Eleven is out. We're 12 going to go to the point Felix made. 13 CHAIRPERSON PRENTICE: All right. Then 14 let's go to 12. Any problems with 12? 15 MEMBER BARNES: You know, you used the 16 example in your presentation of, for example, a 17 country in Africa where the risks, the background 18 risks, for a child might be higher than in the United 19 States. How would that logic apply, though, if the 20 country in which we were going to do the research or 21 were proposing research actually had risks that were 22 lower than that of the United States? It just might 73 1 be worthwhile illustrating that. 2 MEMBER FISHER: My comment to that would 3 be that the research would be okay based on our 4 perspective, but then that's when I guess other 5 standards if the country or they were going by 6 international guidelines there were other standards, 7 but as far as I know, there were no others. 8 For those who do international research -- 9 CHAIRPERSON PRENTICE: Were you going to 10 make a comment? 11 MEMBER FISHER: I just think it would be 12 impossible to -- I think this, remember, is bottom 13 line the degree of risks that kids can be exposed to. 14 I think it is pretty minimal. 15 Even if there was a country to which there 16 were less risks involved than the normal healthy 17 average child, I still think that child would be 18 relatively safe. 19 Now, the country itself could say, "We 20 don't accept that." Then it becomes relative again. 21 So we have to be careful. I just don't know how we 22 would include it. 74 1 CHAIRPERSON PRENTICE: Okay. Further 2 comments? 3 (No response.) 4 CHAIRPERSON PRENTICE: All right. Why 5 don't we move on to 406? 6 MEMBER BARNES: Can I make a make a motion 7 for conditional acceptance of these recommendations, 8 -- 10 and 11 we took out -- with the amendments as 9 they were stated as we went through, conditional 10 approval understanding, as Susan said, that at the end 11 of this entire process, there will be an opportunity 12 if the committee wants to revisit any of the 13 particular recommendations? 14 CHAIRPERSON PRENTICE: Is there a second? 15 MEMBER ADAMS: Second 16 CHAIRPERSON PRENTICE: Lots of seconds. 17 Any thirds? Any further discussion? 18 (No response.) 19 CHAIRPERSON PRENTICE: All of those in 20 favor? 21 (Whereupon, there was a chorus of 22 "ayes.") 75 1 CHAIRPERSON PRENTICE: Any opposed? 2 (No response.) 3 CHAIRPERSON PRENTICE: Any abstentions? 4 (No response.) 5 CHAIRPERSON PRENTICE: Motion carries. 6 Okay. Go ahead. 7 MEMBER FISHER: Now we get to the fun 8 part, which is totally, totally hard, although it will 9 look as if there is a stream of continuity here. 10 There is, but I think it begins to raise questions. 11 I think Susan and I were talking before 12 that sometimes in the subcommittee, the people that 13 are really experts and have had years and years on 14 IRBs to have experience, they can always think in 15 terms of examples where it would or would not fit or 16 how to modify. 17 One of the things that I think becomes 18 particularly important as we start moving to 406 and 19 405 that I think Susan and I both think is that we 20 should try to keep in mind how the average or the 21 novice IRB person or investigator would understand 22 what we are trying to do and make the types of 76 1 decisions that are important to ensure that good 2 research moves forward but that children are not 3 exposed to risk that is not appropriate. 4 Here based on what Ernie said before, this 5 is non-beneficial research, right, 406? Okay. So 6 this is research that does not hold out the direct 7 benefit for the individual subject. Okay. 8 So just to review very briefly because we 9 are going to go over them in detail, there are a 10 number of protections built in to 406 in the sense of 11 strict criteria. It has to be only a minor increase 12 over minimal risk. 13 The procedures themselves that are being 14 introduced by the research have to be commensurate 15 with those inherent in the actual or expected medical, 16 dental, psychological, social, or educational 17 situations. 18 The intervention or procedure has to be 19 likely to yield generalizable knowledge about the 20 subject's disorder or condition. And it has to be of 21 vital importance for the understanding or amelioration 22 of the subject's disorder or conditions. And you 77 1 need, where feasible, to have child consent and 2 parental permission. 3 So this all looks great except for the 4 fact that no one knows what any of these terms mean. 5 But there is the notion here that greater protections 6 are needed when you move above minimal risk for 7 research that children will not get any possibility of 8 direct benefit. 9 Now, there is a justification and caution. 10 The subcommittee was very much in favor of having a 11 406 because minor increment over minimal risk is the 12 regulatory -- now, the justification if you look at 13 the middle one is "Foreseeable benefit to an 14 identifiable class of children may justify a minor 15 increment of risk to research subjects." And we agree 16 with the national commission, and we endorse the 17 necessity for a 406. 18 At the same time, we also agree that it 19 needs more caution because it is the regulatory 20 threshold for independent IRB approval. Anything 21 above minor increment that is not of direct benefit 22 must go to a 407 or be rejected from an IRB. So it is 78 1 the only -- it is the next step and the only step that 2 an IRB can independently approve non-beneficial 3 research. 4 At the same time, simply because a child 5 has a disorder or condition from a justice perspective 6 does not mean it's fair to expose them to higher 7 degrees of risk in and of itself without all of the 8 protections that would be in there. 9 Okay. So what does minor increment mean? 10 The problems with minor increment are similar. We 11 don't want to underestimate the type of risk. If we 12 underestimate the definition of minor, then we may be 13 exposing children to risk that is unethical and 14 inappropriate. 15 At the same time, if we overestimate the 16 amount of risk, we are depriving children of research 17 necessary to their health and welfare. We're moving 18 investigators once again into potentially 19 overestimating the direct benefits of such procedures 20 in order to be able to rationalize a study under 21 something that IRBs can approve or we may be pushing 22 IRBs into submitting protocols appropriate for 406 79 1 into a 407 review. 2 So we want to make sure, number one, that 3 there is a consensus, which has always been our goal 4 throughout our discussions of Subpart D, what can OHRP 5 provide in guidance that would help create a greater 6 consensus and transparency to meaning and at the same 7 time not lose the protections that are necessary for 8 children? 9 Should minor increment -- now we're back 10 to the uniform versus relative standard argument, but 11 now it's whether or not we should apply it to minor 12 increment. The uniform standard would be that the 13 increment is the same for all children indexed to the 14 normal average healthy child living in safe 15 environments. 16 Remember that it's minor increment over 17 minimal risk. So the baseline, the index for whether 18 something is minor is based on our definition of what 19 minimal risk was. That's why we felt that a uniform 20 definition was very important, but we need to 21 understand that minor now needs to be indexed to the 22 daily life or routine experiences of the normal 80 1 average healthy child living in safe environments. 2 A relative standard would say that the 3 increment is minor but relative to the risks and 4 magnitudes of the harms that the individual 5 participant population experiences in and of 6 themselves. 7 So it would be minor, but it's saying that 8 it's bringing in those terms "commensurate" and really 9 saying that commensurate qualifies the minor increment 10 over minimal risk. What is minor? And you can see 11 there are problems with this. 12 Okay. We proposed a uniform standard. We 13 said IRBs should use a uniform criterion to determine 14 whether the risks of an experimental procedure present 15 a minor increment over minimal risk. Minor increase 16 should be indexed to the uniform minimal risk 17 criteria, as I just said. And risks of daily life or 18 routine medical or psychological examinations to the 19 well child visit are standardized routine, so just to 20 place this in context. 21 But we can't be finished here. Just like 22 with the minimal risk, everything depends on how we 81 1 are explaining what we mean by minor, commensurate, 2 vital, and all of those other things. But we are 3 recommending uniform. 4 Now, once again we are saying uniform has 5 to be an equivalence criteria. And we are going to 6 try to give an example of what minor might be. But 7 even when we give the examples of minor, once again, 8 the decision of an IRB has to be whether or not the 9 type of increase in risk that the experimental 10 procedure is posing is equivalent to the magnitude of 11 pain or discomfort in our examples, the probability of 12 risk, the duration, the cumulative effect, and the 13 reversibility of harm. 14 So, once again, if we are going to have a 15 uniform standard, there is not going to be any one 16 thing that "Oh, it's not this procedure. So, 17 therefore, it will not be acceptable." It has to be 18 an equivalence. But the definition of minor is very, 19 very hard. 20 Interestingly enough, -- this may have 21 been incredible wisdom on the part of those who 22 created the 1981 -- the preamble to the final rule 82 1 left the determination of minor increase over minimal 2 risk to the IRBs. And we can certainly see why after 3 our deliberations. 4 Now, NHRPAC, IOM, people have tried to 5 define it, but the words they use I don't think are 6 really very helpful, as we discussed last time, "just 7 a bit more," "a little more than minimal," "a slight 8 increase." You know, you could think of lots of words 9 that mean minor, but I don't think that is helpful. 10 So our proposal 14 -- and here is where we 11 need a lot of input -- we tried to say, is there 12 something like the well child visit that we could use 13 as an indexing for minor, what we mean by "minor"? 14 So we struggled with looking at that, and 15 we came up with there are certain procedures in 16 medical and psychological examinations that are 17 considered minor procedures. So they are routinely 18 performed in the diagnosis of common medical or 19 psychological conditions. 20 And we struggled with, could this be some 21 kind of index for what we mean by "minor increment" to 22 which IRBs could look at whether or not the increment 83 1 is equivalent to those types of increments. 2 Okay. So here are some examples that the 3 subcommittee came up with. Minor procedures could be 4 associated with or minor increment could look at these 5 as a reference: pain or discomfort of low intensity 6 and short duration; physical restraints for younger 7 children; medication, such as the use of local 8 anesthesia or conscious sedation; diagnostic questions 9 exploring trauma or depressive symptoms in greater 10 depth than standard well child visit or psychological 11 tests; -- remember once again reversibility will come 12 into play there -- IV fluids; CT scan; lumbar puncture 13 obviously with the things that you do to make it less 14 stressful and painful; repeated blood draws; 15 medication with a good anticipated safety profile, 16 like antibiotics prolong their intensive psychological 17 evaluations. 18 What minor increment is not. It is not 19 procedures associated with an appreciable risk of 20 death, disability, or serious adverse effects. It is 21 not procedures that require in-patient monitoring or 22 follow-up evaluation for the procedure itself. It is 84 1 not general anesthesia, repeated CT scans or organ 2 biopsy. 3 Okay. So that is where we are struggling 4 with minor. And your feedback as to whether or not we 5 are on the right track would be really important. Is 6 there a way to provide an index of what we mean by 7 "minor"? 8 Now we are on to what is condition. 9 Condition is very important because condition limits 10 who is going to be allowed to be exposed to minor 11 increment because the regulation says only those kids 12 with a condition or disorder can be exposed to the 13 minor increment. 14 Okay. So one of the things we have to be 15 careful about is, on the one hand, we want to ensure 16 that children are not unjustly exposed to greater 17 risk, that just because you live in a violence-prone 18 area, it is okay or just because you have cancer or 19 some other disorder, it is okay to give you this 20 increase. 21 However, at the same time, we want to 22 avoid definitions that would not allow us to do 85 1 research on children's conditions or disorder or do 2 research in general for children in general, like 3 vaccine research or other types of things that may be 4 very relevant, some of the things that -- let's say 5 all infants are exposed to a certain degree of risk. 6 Let's say we don't know about sudden death 7 syndrome. So all children may be exposed because we 8 are not sure what the risk predictors are. Would it 9 be okay to do research on that population, to label 10 all infants as having the condition? 11 So this is the problem. The IOM attempted 12 to struggle with what we are attempting to struggle 13 with. How do you have a definition that does not 14 limit good research on the normal average child who 15 may within a particular research question have the 16 condition that is relevant versus how do you make sure 17 we're just not including everybody? That is a 18 meaningless term. 19 Here this is more where we did address 20 your concern, Felix, and I am glad you pointed out 21 that we needed to address it in 404. Our proposal 22 here is that, similar to the IOM, the term "condition" 86 1 should be interpreted as referring to a specific or 2 set of specific physical, psychological, 3 neurodevelopmental or social characteristics that in 4 an established body of scientific or clinical evidence 5 that shown to negatively affect children's health and 6 well-being or to increase their risk of developing a 7 health problem in the future. 8 So here we are not excluding the normal 9 healthy average child from research to which there is 10 evidence that that group of children at a particular 11 age may be at risk for a disorder affecting or a 12 health problem that is affecting all children. 13 The protection that comes under here is 14 that, number one, it has to be a negative risk. There 15 has to be a risk that something negative might happen 16 to that population. And, number two, there has to be 17 evidence that the way the investigator defined the 18 subject population is consistent with scientific or 19 clinical evidence that, in fact, that population is at 20 risk. So it anchors it in that way that we talked 21 about before for 404. 22 Now we go to the definition of vital 87 1 importance. What does that mean? In the regs, it 2 says it has to be of vital importance for the 3 understanding or amelioration of the subject's 4 disorder or condition. 5 Our proposal is that in order to be 6 considered vitally important, knowledge gained as a 7 result of the research must have clear implications 8 for understanding the etiology, prevention, diagnosis, 9 pathophysiology, or amelioration of the condition. 10 It has to have clear implications for 11 developing treatment for the condition and/or it has 12 to have clear implications for determining future 13 directions for research on the condition. The term 14 "clear" here I think is different from what would be 15 required for 404. And also it has to have some 16 applied value but really not because also determining 17 future directions for research. 18 The rationale that we used for the clear 19 is that exposing children with a disorder or a 20 condition to a greater level of risk than normal 21 healthy average children living in safe environments 22 should have a higher criteria for scientific and 88 1 social benefit than minimal risk research. 2 Now we get to the term "commensurate." I 3 find this one in terms of its application very 4 confusing, as I think the subcommittee went back and 5 forth on this. The language on the regulation is that 6 the intervention or procedure presents experiences to 7 subjects that are reasonably commensurate with those 8 inherent than their actual or expected medical, 9 dental, psychological, social, or educational 10 situations. 11 Now, the question that came up and I think 12 I mentioned last time is, does commensurate mean that 13 the risk level -- when you are trying to decide about 14 minor increment, is it talking about evaluating the 15 minor increment to procedures that are commensurate or 16 was it there to protect for informed consent? That 17 is, parents and children but parents, most of all, 18 needed to have some experience with the procedure or 19 were likely to so that they could give some kind of 20 informed consent about what that procedure would be. 21 So we propose that the term "commensurate" 22 should be applied to help ensure that parents; 89 1 guardians; and, when feasible, children are familiar 2 enough with the type of research procedures that will 3 be employed to make an informed participation decision 4 and that the term should not be interpreted to imply 5 that the upper limit of minor increment of a minimal 6 risk can vary depending on the child's previous or 7 expected experience because that would make it 8 relative. 9 I have to say that I think this is 10 somewhat confusing because if we go back to the 11 language of the regulations, it says, "with those 12 inherent in their actual or expected medical or 13 dental." So if it's expected, it doesn't mean that 14 the parent already had experience with this procedure. 15 It means that they might. And so in some sense, the 16 research could serve as an educative way of helping 17 them consent to the procedure itself. 18 I think that the language, even though the 19 national commission, I believe, or the preamble -- I 20 can't remember at the moment -- said that -- oh, no. 21 It was the children. The national commission said 22 that commensurate was supposed to be relating to the 90 1 ability of parents to make a good judgment about 2 consent. I'm finding that the expected is not 3 necessarily clear with that expectation. And we had 4 these discussions in our subcommittee meeting. 5 Okay. So we're making this proposal, but 6 i think we need feedback on it. Now, if we are going 7 to use commensurate, once again, we have to use 8 equivalence. It's not that it has to be the exact 9 same procedure that the parent was familiar with or 10 should be expected to but that it is equivalent in 11 magnitude and probability of risk, as measured by 12 duration, cumulative, and reversibility. 13 Okay. Now, here is once again the 14 committee. I think we mentioned this to you last 15 time. I really would like feedback on this because 16 the committee continues to debate this issue. 17 By "commensurate," do we mean actual or 18 vicarious experience? Should it be something the 19 child themselves will experience or can it be 20 vicarious? And here is the example. 21 Based upon the commensurate standard, the 22 use for solely research purposes of a hyperglycemic 91 1 clamp might be considered an acceptable minor 2 increment over minimal risk for children with diabetes 3 who had previous experience with the clamp in the 4 course of their treatment. But is it acceptable to 5 have that procedure for a sibling of a diabetic child 6 who had observed his sibling experience in the clamp 7 but was neither diabetic nor had had the experience of 8 the use of the clamp him or her self? 9 The problem here is whether anyone could 10 -- I have problems personally seeing "commensurate" as 11 vicarious. However, at the same time, the problem 12 with 406 is that it rules out normal children who 13 don't have a problem from minor risk research that may 14 be critically important not for their own disorder but 15 for the disorder of other children. 16 The question is, if we have a conservative 17 interpretation, it means that whenever a normal 18 control or normal baseline is going to be used for 19 minor increment, the normal must go to a 407 review. 20 Remember, because we do component 21 analysis, if that is the right term, Ernie, but the 22 condition, the kids who have the condition, it goes to 92 1 a 406. And when you think about it, it is kind of 2 saying that kids who have a condition can be 3 independently improved for minor increment research 4 but kids who do not must go to a 407. Yet, if we use 5 the uniform criteria, the degree of risk is the same 6 for the two. And the difference really is that they 7 don't have a condition and/or it's not commensurate 8 with their experience. 9 So this is the struggle. Four-o-six 10 becomes a very important bridge to how much we think 11 IRBs should be able to independently approve above 12 minimal risk research, what is appropriate for 407, 13 and how to prevent some things from just being pushed 14 into a 407 criteria, which was one of the things with 15 the Kennedy-Kreiger that begins to show the complexity 16 of trying to figure out where this type of research 17 lies. 18 Okay. So even though we are not exactly 19 sure what all of this stuff means, it did seem like we 20 could have some kind of an algorithm that would be 21 helpful. That is that an IRB would first decide 22 whether or not based on the uniform criteria, whether 93 1 a minor increase over minimal risk existed. If it 2 didn't, then it could be minimal risk research. 3 If it was greater than minor, the IRB 4 could reject it or move it on to a 407. If it was 5 yes, then they would have to say, "Well, based on the 6 absolute criterion, it is a minor increment, but does 7 this child have a disorder or condition?" 8 If the child had a disorder or condition, 9 it could move on in terms of evaluation under 406, but 10 if the child didn't, the IRB could reject it or 11 propose it for a 407 review. Another alternative 12 obviously is to ask the investigators to see if they 13 could minimize the risk. 14 Then the next step is, well, the kid might 15 have a disorder or condition, but is the research of 16 vital importance to that child's disorder or 17 condition? If no, might be rejected; if yes, then we 18 move on to, are the research risks commensurate with 19 the actual or expected situations? If yes, you move 20 on; if no, reject or go to 407. And then, of course, 21 are parental permission or assent procedures adequate? 22 I think the important part of this 94 1 algorithm right now for you to look at is that even 2 though we need approval and we need further discussion 3 on definition is that it is anchored in a notion of a 4 uniform criteria for minor increment over minimal risk 5 because that comes first. Before you consider whether 6 or not the child even has a condition, you are 7 considering whether or not it is a minor increment. 8 So I think that is what is important to think about, 9 just conceptually whether or not we choose a uniform 10 or relative standard will have implications for what 11 is going to be the reference point for all of these 12 other definitions. 13 And here we are again with our summary. 14 CHAIRPERSON PRENTICE: Yes? 15 MEMBER KORNETSKY: I just wanted to bring 16 another based on the committee's work in a very 17 practical way. And I used to think that the issue of 18 minimal risk in the definitions is problematic, but it 19 really is. I think the crux of this in a very 20 practical way, a lot of it boils down to this issue of 21 commensurate. 22 I thinking about it, even in the 20 years 95 1 that I have been working with IRBs, the way that 2 pediatric research is being done, which has very 3 positive effects, really has changed since the 4 regulations have been written, where perhaps we are 5 now wanting to involve more normal children and for 6 good reason. I think how pediatric research has 7 progressed shows that we can do a lot more in 8 pediatrics. 9 So this part of the commensurate within 10 the regulations is very, very problematic. It comes 11 up constantly. Towards the end of the discussions, 12 actually through e-mails, there were a couple of our 13 members that said if all of the parts in the pediatric 14 regulations, if we can say, you know, what part could 15 be thrown out or does it still make sense, there was 16 some even discussion about that. 17 So to me -- and it is probab