1 1 2 DEPARTMENT OF HEALTH AND HUMAN SERVICES 3 + + + + + 4 SECRETARY'S ADVISORY COMMITTEE ON 5 HUMAN RESEARCH PROTECTION 6 + + + + + 7 MEETING 8 + + + + + 9 MONDAY 10 JULY 26, 2004 11 The Advisory Committee met in the Franklin Room 12 in the Sheraton Four Points Hotel, 1201 K Street, N.W., Washington, D.C., at 8:30 a.m., Ernest Prentice, Ph.D., 13 Chairman, presiding. 14 PRESENT 15 ERNEST D. PRENTICE, Ph.D. Chair BERNARD A SCHWETZ, D.V.M, Ph.D. Acting Executive 16 Secretary CATHERINE SLATINSHEK, M.A. Executive Director 17 THOMAS L. ADAMS, CAE Member MARK BARNES, J.D., L.L.M. Member 18 CELIA B. FISHER, Ph.D. Member E. NIGEL HARRIS, M. Phil., M.D., D.M. Member 19 NANCY L. JONES, Ph.D. Member FELIX A. KHIN-MUANG-GYI, Pharm. D. Member 20 SUSAN KORNETSKY, M.P.H Member MARY L. POLAN, M.D., Ph.D., M.P.H. Member 21 SUSAN L. WEINER, Ph.D. Member 22 23 NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 2 1 2 Ex Officio Members 3 HOWARD L. BRADLEY Social Security Administration 4 FRANCIS X. BRICKFIELD Central Intelligence Agency 5 FRANCIS D. CHESLEY, M.D. Agency for Healthcare 6 Research and Quality 7 ROGER CORTESI U.S. Environmental Protection Agency 8 PATTY DECOT U.S. Department of Defense 9 HELEN DERAMOND U.S. Department of Education 10 SUZANNE GAYNOR U.S. Department of Housing and Urban Development 11 DAVID LePAY, M.D., Ph.D. Food and Drug 12 Administration 13 AMY P. PATTERSON National Institutes of Health 14 DAVID SHORE National Institutes of Health 15 16 17 18 19 20 21 22 23 NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 3 1 I-N-D-E-X 2 Welcome and Opening Remarks, Ernest Prentice, 3 Ph.D., Chairman, SACHRP...............................4 4 Report on Issues, Bernard Schwetz, D.V.M., 5 Ph.D., Director, OHRP.................................6 6 Overview of Charges to Subcommittees, Ernest 7 Prentice, Ph.D., Chairman, SACHRP....................11 8 Public Comment..............................................14 9 10 Subcommittee on Research Involving Children, report/issues........................................15 11 12 Subpart C Subcommittee report/issues.......................129 13 Public Comment.............................................225 14 15 16 Summary of day's activities................................239 17 18 further discussion 19 20 Adjourn....................................................325 21 22 23 NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 4 1 P-R-O-C-E-E-D-I-N-G-S 2 8:36 A.M. 3 4 CHAIRMAN PRENTICE: Good morning, 5 everybody. My name is Ernie Prentice. I'm the chair 6 of SACHRP, the Secretary's Advisory Committee for Human 7 Research Protection and I would like to welcome 8 everybody, welcome to members of SACHRP, welcome to our 9 ad hoc members and most particularly, welcome to the 10 public who have attended today. We thank you for your 11 presence. 12 Before we begin, I would like to 13 acknowledge the hard work of all of the OHRP staff who 14 have provided support for SACHRP. They keep us on 15 track. They provide expert advice. They develop the 16 fantastic briefing books that you all have, so I really 17 think that we them a debt of gratitude. Thanks very 18 much for all of your help. 19 I always begin these meetings with 20 reminding us about our charter and we are charged with 21 advising the Secretary on matters concerning the 22 protection of human subjects and Secretary Thompson has NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 5 1 asked us to emphasize, in particular, additional 2 protections for special populations such as neonates, 3 children, prisoners, decisionally impaired, pregnant 4 women, embryos/fetuses and also to look at 5 international studies, investigator, conflict of 6 interest and various OHRP activities. 7 So we have tried to diligently pursue 8 this particular charter ever since we first convened. 9 And today, you will see evidence of that progress. 10 I also want to remind everybody once 11 again, and I always have this quote on these 12 introductory comments that Secretary Thompson has 13 stated "we must make sure we allow science and medical 14 research to advance for the good of all Americans, but 15 not at the expense of the people who participate in 16 clinical trials." And of course, we know that there's 17 been lots of negative publicity over the years 18 concerning participation in clinical trials and we want 19 to make sure that we instill in the American public 20 confidence in the fact that they're going to be 21 protected, if they participate in research. 22 These are the members of SACHRP and NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 6 1 they've worked very hard in carrying out their 2 particular charges and they're all around the table 3 here with one exception, Dr. Hauser could not be with 4 us today. 5 Dr. Schwetz is the Executive Secretary of 6 SACHRP and he and I and the rest of the members of 7 SACHRP work very, very closely together. 8 Cathy Slatinshek, of course, she keeps us 9 all on track. Thank you, Cathy. We couldn't do what 10 we do without you. So we really appreciate you. 11 Thanks to the ex officio members of 12 SACHRP, Dr. Schwetz meets regularly with all of these 13 ex officio members. They talk about common issues of 14 interest and concern and that information is then 15 brought back to SACHRP. So it really is a coordinated, 16 integrated effort across agencies within the Federal 17 Government. 18 Next we have Dr. Schwetz who is going to 19 give is a report on issues. 20 Bern, would you take over, please? 21 DR. SCHWETZ: Thank you, Ernie. And good 22 morning to all of you and I appreciate also the public NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 7 1 and all of the SACHRP members and ex officios being 2 here. I particularly want to thank the Subcommittee, 3 the committee and the Subcommittee members for all the 4 hard work that you're doing. 5 Ernie, it's nice of you to comment on the 6 help of OHRP people. When the committee and 7 Subcommittees do the amount of work that you do, it's 8 easy for us to be supportive and help with what you're 9 doing because we know we're getting something back 10 that's valuable, not just to us, but to the whole 11 community. So we really appreciate the hard work that 12 all of you are doing, as a committee and as members of 13 the Subcommittees. 14 I would assure you that as we have 15 deliberations within OHRP these days, the 16 recommendations, the discussions that we have here at 17 the SACHRP meetings are part of our thinking on a daily 18 basis and that's how I would hope this would turn out. 19 In addition, I would say that we are now 20 beginning to move information from SACHRP deliberations 21 into the Office of the Secretary directly through 22 letters and through briefings, so I think that's also a NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 8 1 good sign that your message, your thoughts are being 2 delivered directly up into the Office of the Secretary. 3 Let me say just another word about the ex 4 officios because we do meet on a regular basis and 5 there are two activities in particular that the ex 6 officios are working on that have to do with SACHRP 7 business, SACHRP discussions and one of them is the 8 adverse event reporting process. You recommended that 9 we would, between FDA and OHRP that we would work on 10 guidances, on procedures for IRBs to use and the 11 research community to use relative to the reporting of 12 adverse events. We're working on that in both FDA and 13 OHRP and we're making progress. But the ex officios 14 are working on a complementary piece of this to help 15 work with terms between the two dictionaries that are 16 commonly in use for the terms that might be used to 17 describe adverse events, to bridge them and make sure 18 that they're the least confusing that we can have it 19 be. So the ex officios are working on definitions of 20 terms. They're working on the format and content of 21 adverse event reports. So that we can use them most 22 efficiently and most effectively, but also in addition NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 9 1 communications regarding adverse events and adverse 2 event reports. So the ex officios are doing something 3 that I think will help move this process forward in a 4 very good way. 5 We also continue to discuss the 6 distinction between research and public health 7 surveillance, research and quality improvements, the 8 issue being research versus non-research in some cases. 9 An issue that seems to be true within most of the 10 federal agencies that are part of the common rule 11 activities and the more we talk about it, the more we 12 discover that this is really an issue across many 13 agencies and if it is an issue within federal agencies, 14 I have to believe that it probably is within state 15 agencies and other places where the money goes from 16 federal agencies to carry on public health activities. 17 So that continues to be a topic of discussion. 18 Let me just highlight some other things 19 very quickly. We continue to work on a recognition and 20 a celebration, in effect, of the Belmont Report. And 21 it will culminate with two things. One of them will be 22 an event at the Great Hall of the Humphrey Building, NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 10 1 the headquarters of DHHS downtown on November 16th that 2 will be a public recognition from the standpoint of HHS 3 and others to recognize the importance of the Belmont 4 Report. In the meantime, we are interviewing many of 5 the -- all of the members of the National Commission on 6 tape to create a video record of their recollection, 7 their thoughts, so that this is all captured. And then 8 out of that we're going to develop an educational tool 9 that we will use within OHRP so that people know who 10 the National Commission members are and it reinforces 11 the importance of the Belmont Report and the importance 12 that it is not just as a report, but the fact that it's 13 still is influencing all of us on a daily basis. 14 So November 16th in the Great Hall at Humphrey 15 Building. 16 There's another translation of that 17 ethics consideration and that is that we have heard you 18 and the Subcommittee say that Subpart C has problems, 19 but it needs to be rewritten. And one of the things 20 that we have been discussing within OHRP and with the 21 Subcommittee on Subpart C is the advisability of not 22 starting to rewrite from the standpoint of regulations, NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 11 1 but going back to a discussion of the ethics that would 2 be the basis for rewriting a Subpart C. And we have 3 had some discussions, I've discussed it with all the ex 4 officios and with other government agency 5 representatives. I've talked to the IOM people. We're 6 trying to move this concept forward, whether it would 7 be one where we would ask for help from an IOM 8 committee or go some other route, but to start from 9 ethical considerations for research on prisoners as a 10 basis for how we would move forward. 11 Another topic, you are probably aware 12 that we have an NPRM out for mandatory registration of 13 IRBs. This would be a joint effort between FDA and 14 OHRP in developing a database for mandatory 15 registration of IRBs. I think this would be a step 16 forward in our efforts to try to understand the 17 dimensions of this enterprise and know who the players 18 and how to reach them. That was issued some weeks ago 19 and I think it closes on September 4th of 6th. It's in 20 those first few days of September that we're seeking 21 public comment on the proposal for mandatory 22 registration. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 12 1 We are in the business of scaling up to 2 write more guidances within OHRP, something that I have 3 mentioned to you before. We're bringing more help in 4 to do that from the outside, people who have experience 5 with the regulations and we're also doing some 6 streamlining within OHRP to be able to use that outside 7 help to move forward and getting some more guidance as 8 written and I would appeal back to you again that if 9 you have, if you want to make suggestions on priorities 10 for guidances, we would welcome your recommendations 11 for what you would suggest are the highest priorities 12 that we should be working on. And I would extend that 13 not just to the SACHRP or the Subcommittee members, but 14 to the public and the rest of you as well, to give us 15 advice on what the highest priorities. 16 Just one last thing and I would mention 17 that I continue to give thought, to ask questions, to 18 raise discussion as I have audiences on the issue of 19 how do we prevent the next tragedy that someone would 20 be harmed to the extent that it was something that was 21 a problem in terms of the execution of the study or a 22 surprise that we should have anticipated. How do we NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 13 1 anticipate the next tragedy and therefore take steps to 2 avoid that one or others? Obviously, the tragedies, 3 when they occur, get a huge amount of attention and 4 that kind of attention isn't the right basis for making 5 decisions for how we're going to do this work from then 6 on because there are other near misses or there are 7 other things that happen around the threshold of 8 compliance and injury on a daily basis. And it isn't 9 the given that when a tragedy occurs and new 10 regulations get written that that provides the best 11 protection for all of the enterprise. 12 So I'm trying to get people to think more 13 about how could we be anticipating that next event? 14 How do we change the culture of how we do our work so 15 that we take advantage of near misses when they do 16 happen and that we might do the best we can rather than 17 just say well, there's going to be. It's going to 18 happen and we don't know where and we have to wait for 19 it. I'm hoping we can do more than that. 20 Ernie, with that I'll quit and turn it 21 back to you. 22 CHAIRMAN PRENTICE: Thank you, Bern. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 14 1 I'd like to next provide an overview of 2 the charges to the SACHRP Subcommittees. Currently we 3 have two Subcommittees that are working on pursuit of 4 the Secretary's charge. One is a Subcommittee dealing 5 with research involving children. And the second is a 6 Subcommittee dealing with research involving prisoners. 7 I'm sure that the members of SACHRP 8 probably don't' need this, but perhaps members of the 9 public are unfamiliar with what the Subcommittees are 10 doing. So in terms of the Subcommittee on research 11 involving children, this is the updated charge: to 12 provide recommendations for consideration by SACHRP on 13 interpretations of the requirements of 46.404, 405, 406 14 under Subpart D in order to strike the right balance 15 between neither under protecting children nor 16 overprotecting children. 17 Now I say this is an updated charter 18 because the Subcommittee on research involving children 19 has already sent recommendations with regard to the 407 20 Panel review closest to the Secretary. That was their 21 initial charge. That's what they concentrated their 22 initial efforts on. That work has now been completed. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 15 1 Again, it's gone to the Secretary and I'm optimistic 2 that the recommendations will be implemented in a 3 timely way by OHRP. 4 The next task, I think is probably more 5 complicated. And that is to actually interpret the 6 requirements under Subpart D. I think I mentioned at 7 some point in time in earlier meetings that Subpart D 8 was issued in 1983 and we've been struggling basically 9 for the last 21 years on how to interpret Subpart D in 10 order to adequately protect kids in research. So this 11 is a very, very important task for the Subcommittee. 12 And they're going to be producing a report for us to 13 consider today on their work thus far. 14 The two chairs, co-chairs are Celia 15 Fisher and Susan Kornetsky and I would like to thank 16 you for all your hard work and all the hard work of 17 your Subcommittee. You've done a wonderful job. 18 The next Subcommittee is research 19 involving prisoners and I guess for anybody who has not 20 seen this slide before I suppose I ought to tell you 21 what it is. This is actually a prisoner involved in a 22 malaria experiment. These are a couple of jars filled NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 16 1 with malaria-containing -- malaria-infected mosquitos. 2 You can see the prison bars and this is the 3 investigator. Bern talked a little bit about Subpart 4 C. The Subcommittee is charged with making 5 recommendations on the interpretation and 6 re-interpretation and ultimately revision of Subpart C 7 in order to ensure that the regulations do not obstruct 8 ethically and scientifically appropriate research 9 involving prisoners. 10 The Subpart C Subcommittee in 11 consultation with Dr. Schwetz totally agrees that 12 really it would be a good idea to have the IOM look at 13 this issue to try to determine what ethical 14 underpinnings should exist in order to adequately 15 revise Subpart C. So we're looking forward to the 16 IOM's work in terms of producing a report. 17 And the two co-chairs are Mark Barnes and 18 Nancy Dubler. 19 Mark, thank you for all your hard work. 20 I don't think Nancy is here yet, but thanks for all of 21 your hard work. It's absolutely a fascinating 22 Subcommittee to be on. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 17 1 This is going to be the overview of the 2 meeting agenda for today. We've already gone through 3 the welcome, report on issues, overview of charges to 4 the Subcommittee. We're going to have a public comment 5 period. We've decided to have a public comment period 6 before we actually begin the substance of the meeting. 7 We want anybody that has something that they would like 8 to say to SACHRP, we want to give them the opportunity 9 to provide that advice or questions to SACHRP. 10 And then we'll go into the Subcommittee 11 on research involving children at 9:30. We'll take a 12 break at 10:30. We'll continue with the children's 13 report at 10:45. Lunch is at 11:45. There are by the 14 way SACHRP members, there are menus here that you are 15 supposed to indicate your preference for lunch. Then 16 at 12:45 after lunch we'll begin with the Subpart C 17 Subcommittee report. There will be a break between 18 2:45 and 3:00. We're going to have a second public 19 comment period at 3 o'clock and then there will be a 20 summary of the day's activities between 3:30 and 5 and 21 we'll adjourn at 5. 22 Okay, now I would like to invite any NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 18 1 members of the public who would like to address SACHRP 2 to indicae your interest in doing so. 3 (No response.) 4 Hearing no indication of such interest, 5 we'll move on. 6 Celia and Susan? 7 DR. FISHER: We are here again for the 8 third time. We're going to be, Susan and I are 9 reporting on the third meeting of the Children's 10 Subcommittee. Our Subcommittee, as you can see, is a 11 wonderful group of experts in child, medical and social 12 behavioral research. We also work very closely with 13 the chair, Ernie Prentice and with OHRP, Dr. Schwetz, 14 Dr. Carome, Cathy and Kelly are incredibly helpful and 15 we benefit from the comments and input of our 16 additional OHRP representatives, as well as our other 17 attendees. 18 I wanted to go over what the specific 19 goals of our last meeting was and what we want to 20 present to SACHRP today. Our goal was to review and 21 develop preliminary proposals for clarification of 22 Subpart D terminology. The terminology we're talking NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 19 1 about are those that you see in 404 and 406, language 2 such as minimal risk, minor increase over minimal risk, 3 condition and vital. 4 The reason that this is so important is 5 that consensus of IRBs for these terminologies are 6 critical for interpreting all of the four different 7 classifications of the review of research under Subpart 8 D and so they're all interrelated. So I'm going to try 9 to take you through our thinking. 10 The other thing, we have stated this in 11 terms of proposals rather than recommendations because 12 we feel that our work is on-going, but it is very 13 important for the Subcommittee to get SACHRP feedback 14 on whether or not for each of the proposals we are in 15 the right, we're going in the right direction. 16 And so what we're going to do is we're 17 going to spend the first half of our time talking about 18 the terminology associated with 404 which is minimal 19 risk and as you can see we have 11 proposals about that 20 and because minimal risk is the foundation on which 21 minor increment over minimal risk is we will then after 22 asking you for your specific feedback on the minimal NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 20 1 risk discussions, then we'll go to the 406 with all the 2 other terminology. 3 So just to remind people what 404 says, 4 DHHS will conduct or fund research in which the IRB 5 finds that no greater than minimal risk to children be 6 presented only if the IRB finds that adequate 7 provisions are made for soliciting the assent of 8 children and parental permission. 9 Now what's important to keep in mind is 10 that this applies to research in which there is no 11 direct benefit for children. And in some sense, it 12 affords the weakest protections because the only 13 protection in addition to ensuring that the research is 14 posing to more than minimal risk is parental consent 15 and child assent. So because of that and because it's 16 also the foundation for the other classifications of 17 children's research, as you will see, we thought about 18 approaching it from a very conservative stance. 19 And when I say conservative, what I mean 20 is a position on uniform versus relative risk and what 21 we need to think about -- well, I'll take you through 22 the history a little, but the uniform versus relative NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 21 1 risk is do risks -- for the phrase ordinarily 2 encountered in daily life or routine physical or 3 psychological examinations, does that refer to what we 4 called a uniform standard, that is, is it the daily 5 life of the average healthy child or is it a relative 6 standard, that is, the daily life and the magnitude and 7 probability of risks faced by the particular children 8 in the particular research study. So that's what we 9 mean by uniform and relative risk. 10 And I just want to backtrack for a minute 11 and say that in everything we did we were drawing upon 12 the work of others, the National Commission, the NHRPAC 13 report, the recent IOM report was very useful, as 14 you'll see in the power point to our presentations. We 15 also looked at previous notice of proposed rulemaking 16 changes and we also looked at the preamble to the 17 various regulations. 18 So to go into the history of the 19 definition of minimal risk, in 1977 the National 20 Commission, you'll see that there's been an evolution 21 at least within A and potentially D, Subpart D in terms 22 of going for what was a uniform to what is a relative NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 22 1 definition. So in 1977, the National Commission 2 recommended for research involving children that the 3 uniform standard would be applied because here it says 4 healthy children which would be interpreted as not the 5 unique characteristics and potentially vulnerabilities 6 of the children in the research study itself. 7 Then interestingly for HHS as Mike will 8 talk about, the healthy person or uniform definition of 9 minimal risk was incorporated into Subpart C 10 regulations. In addition, in the MPRM for Subpart D, 11 there was a proposal to adopt the National Commission's 12 healthy children standard. 13 However, after receiving comments for the 14 proposed rulemaking, the preamble to the 1981 45 CFR 46 15 changed and it said the terms research -- well, one of 16 the things they decided to do was take out a specific 17 definition of minimal risk from Subpart D. So whereas 18 there is a definition in Subpart C and there's a 19 definition in A, there is no definition of minimal risk 20 as it applies to children in Subpart D. 21 And so they chose to remove the definition of research 22 and minimal risk from the Subpart because it appears in NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 23 1 Subpart A. So of course, what that means is we have to 2 Subpart A and what does minimal risk mean in Subpart A. 3 4 Well, similar to what we've seen before, 5 there was a shift in the minimal risk definition over 6 the years. The NPRM in 1979 suggested using a uniform 7 definition, the healthy individual as the index of 8 minimal risk. However, the preamble to the final rule 9 stated "in light of the public comments on this, 10 however, HHS has reworded the final regulation to 11 reflect its intention that the risks of harm ordinarily 12 encountered in daily life means those risks encountered 13 in the daily life of the subjects of the research." So 14 in 1981, we see from the preamble that there was a 15 shift to a relative standard. 16 And so we have the Subpart A definition 17 which you're all familiar with and what I want to point 18 out is that the final rule language doesn't include 19 specific reference either to a uniform or a relative 20 standard and this ambiguity, even though there's a 21 statement in the preamble, this ambiguity has 22 influenced IRBs and potentially the inconsistency of NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 24 1 IRBs and of course our attention is not on how it's 2 applied to adults, but it's the confusion of how it 3 should be applied to children. 4 Now there are two lines of arguments for 5 the uniform standard for children and the relative 6 standard. Both draw upon the principle,the ethical 7 principle of justice. 8 (Pause.) 9 Okay, and it's very interesting because 10 as Dr. Schwetz was talking about the Belmont Commission 11 remains very important and we've attempted to always 12 kind of bring in what are the ethical issues involved 13 in terms of recommending to you and then to OHRP how to 14 best shape guidance. 15 So the justice argument for the uniform 16 standard is that when research offers no probability of 17 direct benefit, children should not be subjected to 18 greater risk simply because their daily lives are 19 filled with greater risk than healthy children of those 20 living in safe environments. 21 By the same token, individuals who argue 22 for the relative standard also apply principle of NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 25 1 justice and they state that children whose daily lives 2 are filled with greater risk than a healthy or average 3 child should not be deprived the knowledge benefits of 4 research, that we need to be able to do the research on 5 problems of this particular population which may raise 6 the risk. 7 The Subcommittee looked at these two ways 8 of looking at justice and after much discussion 9 concluded that it is a false assumption of the relative 10 argument and the false assumption is that the uniform 11 definition, by having an indexing of minimal risk to 12 the healthy child does not deprive less healthy or less 13 advantaged children from participating in research. 14 Rather now remember, this is the first level of risk 15 that an IRB can acceptably approve for research with no 16 direct benefits to the participant. There are 17 certainly other possibilities for children with 18 disorders or who live in unsafe environments. They can 19 have direct benefit which is 405. We can have research 20 with direct benefit. They also can be involved in 21 research that has no direct benefit, but that can yield 22 generalizable knowledge about their disorder or NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 26 1 condition under 406. And they can also be involved in 2 research that provides an opportunity, understand, 3 prevent or alleviate a serious problem affecting the 4 health or welfare of children under 407. 5 So by having a conservative or uniform 6 index of minimal risk for 404, we are not depriving 7 children with a disorder or condition of research 8 opportunities. 9 So our first proposal is that SACHRP make 10 a recommendation to adopt a uniform standard for the 11 definition of minimal risk for research involving 12 children under Subpart D and of course, we're not 13 recommending that there be a change in the federal 14 guidelines, but how the definition in Subpart A would 15 be applied to Subpart D. 16 Justification. What is our justification 17 for this? Well, approval of procedures as minimal risk 18 should be equally be applied to all children with the 19 protections that accompany the level of risk 20 assessment. 404 permits IRB approval of research 21 offering no direct benefit. It has the fewest 22 subjects' protections and the definition of minimal NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 27 1 risk is a critical baseline level for the approval of 2 the other classifications. 3 There are also precedence in terms of 4 protecting vulnerable populations. We have -- just the 5 fact that we have a special section, B, C and D, is 6 indicative of the fact that the regulations recognize 7 that vulnerable populations need special protections. 8 Why do children as a vulnerable 9 population require greater protections? That might 10 mean that irrespective of how we're applying the 11 minimal risk definition to adults, we need to have a 12 more uniform approach for children. So number one, 13 unlike in Subpart A, the minimal risk definition is the 14 critical baseline for additional and greater risk 15 classifications. The protections offered by minimal 16 risk are less under 404 than any other classification 17 and simply relying on parental permission and assent 18 for children is not the same as relying on consent, 19 informed consent for adults. 20 Children do not have the legal status to 21 consent, in most instances, except when they get to 22 mid-adolescence, their cognitive maturity to understand NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 28 1 procedures and rights are not equivalent to adults. 2 And even when they do understand, the research 3 procedures and rights, they don't have the experience 4 or the authority to make such decisions so that it's 5 important to make sure that 404 has the greatest 6 protections possible. 7 Now what would the language be to help 8 guide IRBs in applying a uniform standard when minimal 9 risk is applied to 404 and any of the other Subpart D 10 classifications? Drawing upon NHRPAC's work and the 11 IOM work, we concluded that the language in which IRBs 12 would -- that would serve as a frame of reference is 13 the normal, average, healthy children living in safe 14 environments, that that would be the index for what is 15 the daily life experience of average, healthy, normal 16 children living in safe environments and what is the 17 routine, psychological and medical examinations that 18 they would be expected to experience. 19 Now why did we choose this particular 20 language? Normal, healthy, average, that language is 21 that children whose lives ordinarily involve greater 22 risks, that is, children who are already taking toxic NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 29 1 drugs to treat cancer or children who live in 2 violence-prone neighborhoods should not be subjected to 3 greater risk than other children under the umbrella of 4 a minimal risk definition. 5 Now we agreed with NHRPAC and IOM to 6 include the terms normal and average, along with 7 healthy, because healthy has a biomedical or diagnostic 8 association and we are not simply talking about 9 children who are physically healthy, but also children 10 that are not living in jeopardy or for some other 11 reason, not in abusive situations or neglectful 12 parents. 13 Living in safe environments, now remember 14 that this is the guide to be as specific as possible to 15 IRBs so what we're trying to mean by this uniform 16 index, so children living in unsafe environments may be 17 exposed routinely to socially permitted risks, for 18 example, exposure to unhealthy levels of lead. But 19 such risks are neither socially desirable nor ethical 20 when they're introduced through experimental procedures 21 defined as minimal risk. 22 Our third proposal is that when indexing NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 30 1 minimal risk to the normal, average, healthy child 2 living in a safe environment, this indexing should also 3 be age graded. That is, that children at different 4 ages, the average risk that they're exposed to is going 5 to differ depending upon whether they're an infant, in 6 preschool, early childhood, so that another thing that 7 the IRB needs to take into account is whether or not 8 these are daily risks or routine examinations that a 9 child of this age would be expected to be exposed to. 10 Now at the same time we recognize that 11 applying a standard of the healthy child living in safe 12 environments may, in fact, be risky for some more 13 vulnerable children. For example, an injection may be 14 minimal risk for a normal, average, healthy child, but 15 be greater than minimal risk for a hemophiliac. So the 16 minimal risk definition indexed to the normal child is 17 a sealing. The IRB cannot approve research that's 18 greater than how we would recommend defining minimal 19 risk. However, when a child is vulnerable to that 20 risk, more vulnerable than the average, healthy child 21 than it should -- those kids should not be subjected to 22 the additional risks. So the IRB needs to take into NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 31 1 account special and unique vulnerabilities that might 2 make a particular research population more vulnerable 3 to the minimal risks of average, healthy children 4 living in safe environments. 5 Now proposal 5 has to do with something 6 that has been confusing among IRBs is what are the 7 procedures that, in fact, the minimal risk applied to 8 children is actually referring to? And as you know, 9 the phrase in the minimal risk Subpart A definition is 10 risks are not greater in and of themselves than those 11 ordinarily encountered in daily life or in the routine 12 examinations. And the issue we were discussing, which 13 also has been discussed by NHRPAC and the IOM is do we 14 mean the exact procedures, the exact experiences of 15 daily life or are we saying that those experiences, 16 research risks -- it could be equivalent procedures, 17 not an actual procedure that the child has experienced, 18 but the procedure has to be no greater in terms of 19 magnitude, probability and some other criteria than 20 children confront in their daily lives. 21 So equivalence means that the IRB does 22 not have to say well is that something that the doctor NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 32 1 ordinarily does to a 9-month-old, but rather for those 2 things that a physician may do in a routine examination 3 is this procedure equivalent in magnitude and 4 probability. 5 Now in terms of determining the 6 equivalence, in addition to magnitude and probability 7 which is within the minimal risk definition itself, we 8 also are recommending, as IOM has that the IRB 9 considered the duration is the duration similar to what 10 the child might experience in routine examinations and 11 what about the cumulative characteristics? In other 12 words, each of the risks that are applied because of 13 the research may in and of themselves be equivalent to 14 the daily life, but their cumulative effect may, in 15 fact, be beyond the magnitude probability and duration. 16 So that's another proposal is to use those as guides. 17 Now not all socially approvable daily 18 risks are minimal risks. So we're trying to grapple 19 with the fact that just because something is part of 20 daily life, does that mean that it's ethical for a 21 researcher to expose a child to that risk and there are 22 certain instances that we would consider not NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 33 1 acceptable. 2 Here's a quite from the IOM report that 3 in action, in children's daily lives, has majority 4 social approval and is legal, does not necessarily make 5 it an appropriate basis of comparison for the 6 assessment of risks to child participants in research. 7 And IOM went on to give an example. Public opinion, 8 state laws or school board policies may permit spanking 9 as a part of school life, but we would not assume that 10 this is an acceptable risk to have, bring kids in a lab 11 and spank them. 12 Similarly, the risks of broken bones are 13 socially acceptable within the context of sports, like 14 football or soccer because society believes that 15 participating in these sports contributes to the 16 child's social and physical development. However, it 17 would not be appropriate to take a child into a lab and 18 hit their head up against the wall or do the kinds of 19 things they might experience in football. However, 20 monitoring a child's heart rate while they're playing a 21 game of football in the school would be minimal risk 22 because the procedure that would be added that's a NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 34 1 research procedure is the monitoring. Okay? So 2 basically then we try to incorporate this under a 3 proposal that would say contextual -- there are 4 contextual constraints for the daily life equivalence. 5 So this proposal would basically state what I had just 6 said. There are some risks that are acceptable in 7 society, but if these same risks would not be 8 acceptable if they were introduced for the purpose of 9 nonbeneficial research and in addition to further help 10 IRBs they can also if they're trying to determine 11 whether something is equivalent to a daily life 12 experience, they can also relate it to whether or not 13 it's equivalent to a routine physical or psychological 14 examination or test. 15 We then turn to what is a routine, 16 medical procedure when it's applied to children. And 17 the Subcommittee agreed with the IOM Committee's 18 conclusion that there is no consensus on what a routine 19 medical examination is. However, what best 20 approximates that is the visit to the physician's 21 office or the pediatrician's office of a well child 22 visit. So a well child visit would be a reasonable NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 35 1 comparison for an IRB to make in terms of level of risk 2 and here are the lists from IOM of some of the 3 experiences that children would have to be age indexed 4 going to a physician. They get a physical examination. 5 They are weighed and circumferenced. There might be 6 an assessment of obesity with a skinfold caliper, 7 collection of blood or voided urine, measurement of 8 heart rate, blood pressure, hearing test, modest 9 changes in diet and schedule, testing of fine and gross 10 motor development, noninvasive physiological 11 monitoring. And what I want you to be thinking about 12 is that there are research procedures that would be 13 equivalent in the magnitude and probability of risk to 14 these. 15 Okay, so the next proposal is what are 16 routine psychological examinations or tests to well 17 child visits and I think we'll hear a little tomorrow 18 from the Social Behavioral Panel about the problems in 19 applying what has traditionally been a medical model to 20 risks in social behavioral research. And so routine 21 child or family history questions of the well child 22 visit typically involve questions to identify health NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 36 1 risks, questions, for example, about diet, lack of 2 seatbelts or a lack of the use of a carseat. Or for 3 adolescents, pediatricians normally ask about sexual 4 behavior, smoking, illicit drug use and other health 5 compromising behaviors. 6 So the Subcommittee, as with the IOM, did 7 not see any reason to assume that simply asking 8 adolescence about high risk behaviors was in and of 9 itself above the minimal risk definition. 10 Another point of guidance is for IRBs, 11 and of course, I don't think it's the IRB's 12 responsibility to go and -- do lit. searches on what 13 kind of psychological instruments are used. The 14 investigator needs in his or her proposal to provide 15 this information to the IRB, but there are certain 16 routine psychological examinations that are utilized: 17 intelligence tests, the kinds of questions that are on 18 that; the kinds of questions that are on infant mental 19 and motor tests, like the WISC or the Bailey; on the 20 reading and math ability tests. There are routine 21 tests for neurological or motor disorders, for social 22 development, family and peer relationship, so emotional NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 37 1 regulations and feelings of sadness and hopefulness. 2 So an investigator can provide this kind of information 3 to an IRB to help them understand and make a judgment 4 about whether or not the minimal risk criteria applies. 5 However, we also discussed the fact that 6 there are exceptions to equating a psychological 7 evaluation to minimal risk and we -- there's this 8 intuitive notion that questions about physical or 9 sexual abuse or other childhood traumas or questions 10 about suicidal ideation or questions about criminal 11 activities that the investigator is legally required to 12 report like child abuse, if there are not protections 13 put in there in the research could be above minimal 14 risk, but the question is where is that gut feeling 15 coming from? And so we discuss that and go to 2 for a 16 minute because that directly addresses that. 17 It's really the extent to which one could 18 anticipate that there would be persistent 19 post-experimental reactions. And whether or not not 20 simply the intuition of the IRB, but whether or not 21 there is some form of scientific or clinical data or 22 evidence that would suggest that there be some type of NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 38 1 post-experimental. So for example, children who have 2 been abused many times or diagnosed with PTSD, post 3 traumatic stress disorder, which then may be elicited, 4 some of the symptoms may be elicited on the basis of 5 asking particular questions. 6 So we're giving that as an example. We 7 would have to get the literature -- suicidal ideation 8 may raise some issues for a child. Now remember, 9 that's not the same as some tests of sadness and 10 hopelessness. But there may be questions to which a 11 routine psychological examination would not end if the 12 child responded in a particular way to an abusive or a 13 suicidal ideation type of question. And if the 14 research is not constructed to follow up, then it may 15 be above minimal risk. 16 Okay, so I'm going to end here. This is 17 the 404. We have a whole bunch of other things for 18 406, but these are the 11 proposal recommendations that 19 we have made for 404 minimal risk and so what we'd like 20 now is for the Committee to give us some feedback. 21 If you want, I can go back to the -- do 22 you want me to go back to the power point pages for NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 39 1 each one of those or -- okay, great. Okay. 2 DR. KORNETSKY: I just want to say Celia 3 did a fantastic job of really summing up what the 4 Subcommittee spent a lot of time talking about. This 5 work has been expanded upon, but I'd also want to 6 comment it's very consistent with the previous work of 7 NHRPAC and IOM. I've been on both of those Committees 8 and I think that what we've done is -- it has matured 9 as we've gone along and we recognize weaknesses, IOM 10 recognized weaknesses in NHRPAC's and we recognize 11 weaknesses and expand it. So sort of looking at the 12 progression of where this has gone, I think there's 13 nothing that's inconsistent. It has only really been 14 built upon. 15 So I think what we're going to do now is 16 open it for questions, again, related to the minimal 17 risk. As Celia mentioned, this is really the basis if 18 we can't sort of come to a common understanding of 19 this, it's going to be even more difficult to talk 20 about on the other categories. So I guess we'll open 21 it for discussion. 22 CHAIRMAN PRENTICE: Thanks, Celia and NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 40 1 Susan, for a very well-organized, thoughtful 2 presentation. 3 I participated in most of your 4 Subcommittee meetings and I'd like to go back to the 5 history of the evolution of the definition of minimal 6 risk. 7 As you know, the National Commission 8 proposed the -- what they referred to as the healthy 9 children standard and then the regulations ultimately 10 came out in the additional protection of children 11 ultimately came out in 1983 and as you know, there was 12 no definition of minimal risk in Subpart D in 1983 and 13 it referred back to the 1981 regulations by more or 14 less default. And the 1981 regulations, made it very 15 clear in the preamble that minimal risk should be tied 16 to the daily life of the individual research subject, 17 so hence my question. 18 What legal precedent, if any, is there of 19 the preamble in the 1981 regulations that apply to 20 adults and children, as well, since there's no 21 definition in Subpart D. What precedence does that 22 establish for us changing the -- or clarifying the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 41 1 definition of minimal risk in Subpart D? 2 DR. FISHER: I think Laura just left, is 3 she here, is Laura here? 4 Okay, I think Laura has been very 5 helpful. I don't know how to say your last name, in 6 terms of helping us with that question. I think Mike 7 Carome also had some statement. 8 My understanding and you can tell me if 9 I'm wrong, is that there are at least two approaches 10 that can be taken. One would be to make a 11 recommendation to change the regulations and actually 12 put in a definition of minimal risk within Subpart D 13 like it is in Subpart C that would state a uniform, if 14 that's what the Committee wanted to approve. 15 Another is to look at how it's been 16 applied in the past, to look at a history of its 17 application and how OHRP has looked at the application 18 of the minimal risk standard in Subpart D as a part of 19 building up, I guess, a case history of its usage and 20 then also if OHRP wanted to put out guidance without 21 changing, there are ways to do that with respect to 22 notices within the Federal Register as to OHRP could NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 42 1 say we are thinking of applying a uniform standard when 2 it's applied to Subpart D asking for feedback and then 3 following feedback in a decision by OHRP to then report 4 or issue guidance on how it's going to be applied. 5 CHAIRMAN PRENTICE: Do you have any 6 feelings as to which way would be the best way to 7 approach this? 8 DR. FISHER: I would leave that up to 9 OHRP. 10 DR. KORNETSKY: And I think it's 11 important to say that we as a Subcommittee were advised 12 to almost take that off the table, to recommend what we 13 think is appropriate and that the recommendations would 14 go to OHRP and that they would determine the best way 15 -- 16 CHAIRMAN PRENTICE: How they do it. 17 DR. KORNETSKY: -- of going about doing 18 it which we all felt comfortable with. 19 DR. HARRIS: I am pretty sure that this 20 must have been debated a number of times, but I'm going 21 to ask and this is with respect to uniform and relative 22 and it deals really with populations of children who NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 43 1 are ill because invariably they're the populations of 2 children from whom relative benefit, if you will, might 3 be greatest from research and where, in fact, you get 4 the greatest number of research questions. 5 Now it is true that you accept the 6 uniform definition, there is still that opportunity for 7 the children. AT the same time, you kick that in to 8 greater scrutiny and greater review, so denying those 9 children the opportunity to participate and studies and 10 for knowledge to begin, at least delaying, if you will, 11 because it's kicked in to some greater review. And so 12 one worries again that by not adopting, by adopting 13 this uniform standard, indeed, it isn't that these 14 children don't have the opportunity for research being 15 done, but indeed it delays it to some degree and it 16 creates a greater opportunity for this research never 17 getting done. 18 DR. KORNETSKY: It doesn't necessarily 19 delay it. And I think you'll see as we -- it could 20 delay it under certain circumstances, but doesn't 21 necessarily and I think from a very practical 22 experience of working at a pediatric institution, NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 44 1 thankfully a lot of the research that is done that is 2 greater than minimal risk does have the potential for 3 direct benefit. So we -- and that is another category, 4 sort of the next category that's up. 5 I think that the area that we get into 6 problems with is when there is no potential for direct 7 benefit and there still is a category that IRBs can use 8 that again would not delay it. It may require 9 additional rationalization and justification on the 10 investigator. But I don't think that this will delay 11 all that type of research. There may be an increase of 12 things that have to be to OHRP, but I personally don't 13 see this as a huge delay. 14 DR. FISHER: Let me also say that the 15 delay would only be, in fact, 404s would typically 16 expedite it. And that's not the case, from what I 17 gather that with children that 404s are not typically 18 expedited. There's a conservative bent on the part of 19 IRBs, but on the other hand in some sense what you're 20 suggesting the relative definition has in some sense 21 becomes a 406 review because for an IRB to determine 22 that a child with a disorder or condition could have NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 45 1 higher than minimal risk or minimal risk for them is 2 higher than for a child, they have to take into account 3 the factors within 406 which is does the child have a 4 disorder or condition? Is this of importance to 5 knowledge about the child's condition? Is it 6 commensurate with their experiences? 7 So in some sense, we would be -- if we 8 keep the relative definition, we're blurring a 9 distinction between 406 and 404 because there's no 10 other way to reach a relative conclusion about 404 11 without using the indexing of 406. 12 CHAIRMAN PRENTICE: Felix? 13 DR. GYI: I wonder if the Subcommittee 14 gave some thought to the application of the expedited 15 review process in pegging certain definitional items 16 with minimal risk? Any thoughts, any guidance? 17 Because clearly this is an area that IRBs really do get 18 into trouble with and have been wrestling with quite a 19 bit. 20 CHAIRMAN PRENTICE: Felix, could you 21 expand -- using expedited review for pediatric 22 research? I mean we are -- expedited review is NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 46 1 permitted in pediatric research. In a lot of the 2 areas, there isn't any distinction made. So if you 3 could just clarify? 4 DR. GYI: Certainly. Clearly, how the 5 interpretation, how the IRB interprets whether a 6 project can be reviewed under expedited review has been 7 an area that they've wrestled with quite a bit. In 8 asking SACRP to make a recommendation regarding 9 adoption of a uniform definition, I wondered if the 10 Committee, the Subcommittee gave some thought to 11 helping the IRBs make some decisions with respect to 12 what can be expedited and what cannot be. 13 DR. FISHER: I think that we didn't 14 discuss that specifically. I think put another way 15 that in accepting the uniform or relative definition, 16 one has to also take into account that it would mean 17 whatever is approved could be expedited. So the 18 regulations permit expedited review of minimal risk 19 research. So we did not discuss the general issue of 20 whether IRBs are being overly conservative in not 21 expediting some research. I think we'll hear something 22 tomorrow, also from the Social Behavioral Panel for NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 47 1 that. 2 But I do think we're up to at the moment 3 is thinking that if -- and I think that's an argument 4 to maintain a conservative or uniform approach to 5 minimal risk because assuming that OHRP may encourage 6 IRBs to take the option of expedited review which they 7 do have, that it's best to have those that can be 8 expedited at a more protective kind of level for 9 children. 10 DR. KORNETSKY: I can't imagine that -- I 11 think a reason that a lot of things are not expedited 12 is because people are so unclear about the definition 13 of minimal risk. I think by clarifying that, if we 14 clarify that, that IRBs will then feel more comfortable 15 expediting research that's minimal risk with kids. 16 DR. FISHER: And we're also hoping that 17 the type of guidance in terms of criteria and examples 18 of what is routine or what are daily life experiences, 19 as well as what are not and the ceiling effect will 20 make IRBs more comfortable after a certain amount of 21 experience in saying ah, this is something that can be 22 expedited. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 48 1 CHAIRMAN PRENTICE: Susan, Celia, what's 2 your feeling about the practices of IRBs across the 3 country, particularly at pediatric hospitals in terms 4 of whether or not they utilize a uniform or absolute 5 definition of minimal risk versus a relative standard? 6 DR. KORNETSKY: I think that has changed. 7 There has been, even though there have been 8 statements, although not in writing at primer 9 conferences and whatever and OHRP, so I think over the 10 last five years I think more have moved to this type of 11 definition, at least from my experience where I think 12 10 years ago you probably really were all over the 13 board. But I think it has been evolving. I think that 14 this is -- there certainly has been NHRPAC, IOM, and 15 even before that there's been discussion. So there 16 will be places out there, I'm sure, that don't want to 17 hear this or have not applied it, but I think that many 18 know that this has been talked about and have been 19 moving towards this. 20 CHAIRMAN PRENTICE: Would you say it's a 21 majority or minority? 22 DR. KORNETSKY: Oh, I don't know. I NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 49 1 would hope that it's more of a majority than we had 2 been thinking about. 3 CHAIRMAN PRENTICE: Is it the 4 Subcommittee's intention to come up with a whole list 5 of procedures that qualify as minimal risk, go way 6 beyond what NHRPAC did and the IOM did? 7 DR. FISHER: No, but we do want to 8 buildup a case, kind of case list, cases that what 9 we're doing at our next Subcommittee meeting is looking 10 at cases and seeing the extent to which the different 11 ways of looking at 404 and 406 and 407 and 405 apply to 12 them. And so we would be utilizing the list that IOM 13 recommended as well as some of the psychological as 14 well as giving cases, but those are only examples of 15 equivalence. They're not -- I don't remember who wrote 16 this, but in one of our readings there was the 17 suggestion that the reason why social behavioral is so 18 much -- appears to have so many more problems than 19 physical for IRB review of minimal risk is that in the 20 guidance there are specific examples of medical 21 procedures so that the IRBs feel more comfortable where 22 all it says is psychological assessments and so they're NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 50 1 drawing upon their own intuitions as to what may or may 2 not. 3 So we are going to provide more examples 4 than NHRPAC did, but once again, they're simply 5 educative. We would never recommend that those be the 6 rules. 7 CHAIRMAN PRENTICE: Susan? 8 DR. WEINER: I just have a comment about 9 the assessment of equivalence and that is the 10 assessment has to do with the procedures, not with the 11 research study so that individual assessments of each 12 procedure within a protocol, for example, have to be, 13 should be made and need to be made. So it's not as if 14 an entire protocol or research study is minimal risk. 15 CHAIRMAN PRENTICE: Mark? 16 MR. BARNES: I just have a hypothetical 17 to ask you about and to see how this would apply and 18 I've gotten this question actually a good bit recently. 19 The CDC funds various behavioral studies, 20 particularly in sexually transmitted diseases and 21 HIV/AIDS prevention among adolescents. And so here's 22 the question. If you have a -- and I'm just trying to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 51 1 get you to understand how this would apply. If you 2 have a situation -- an IRB situation in which there is 3 a study that's proposed for adolescents who are under 4 18 who come to STD clinics because they want to do 5 interviews essentially about sexual behavior and HIV 6 risk factors and that sort of thing and history of 7 sexually transmitted diseases, then two questions. One 8 is is it possible that that study in those 9 circumstances could be minimal risk? And number two, 10 if there were mandatory reporting of a condition that 11 might be triggered by that, would that take it out of 12 your minimal risk analysis? 13 DR. FISHER: I think, first of all, yes. 14 To answer your first question. Those kinds of 15 questions about sexual activity would be considered 16 minimal risk for that particular population, that age 17 group. There's no reason to assume there's risk in 18 asking the question in and of itself. 19 At the same token, remember this is a 20 ceiling and there may be reasons to believe that a 21 particular adolescent population would be vulnerable. 22 So we continue to allow the flexibility. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 52 1 Your second questions, I think goes 2 beyond Subpart D and that question is the extent to 3 which confidentiality issues represent a risk and I 4 think there is a certain amount of history in federal 5 regulations that if it's going to deprive somebody of 6 employment, you know, health insurance, lead to some 7 kind of criminal sanction, those kinds of activities 8 may be looked at as greater than minimal risk. 9 However, what also needs to be considered is what are 10 the protections in place? So it's not just -- 11 remember, it's the probability of risk. 12 One of the issues is whether -- and for 13 child abuse it's different, because child abuse, 14 certificate of confidentiality doesn't waive that 15 obligation, but for illegal drugs or criminal 16 activities, if a researcher received a certificate of 17 confidentiality and was not going to report these 18 procedures, then I would see that as minimal risk. 19 So I think it's a larger question than 20 simply Subpart D about the extent to which the 21 protections that an investigator has proposed for 22 confidentiality is taken into account when evaluating NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 53 1 the level of risk. 2 DR. KORNETSKY: The other thing you would 3 want to look at in determining minimal risk in those 4 situations is the resources and things that are 5 available as part of the research, just to report 6 something and then tell the teenager, they're on their 7 own, deal with it, would not be appropriate and may be 8 greater than minimal risk. 9 A lot has to do within the context of how 10 it's asked, what's done with it and what Celia said. 11 DR. FISHER: And the final component of 12 that is assuming one is not perhaps getting parental 13 permission or if one is getting parental permission and 14 child assent, that it is clear that any report of 15 suspected abuse will be reported. And so an added 16 protection is that it is made clear to anybody 17 participating, if you are -- if you have to follow 18 statutory law, that this is what's going to happen. 19 CHAIRMAN PRENTICE: Yes, Nancy? 20 DR. JONES: Going along some of the 21 comments on providing guidance of what are minimal 22 risks for standardized tests, I do think it's important NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 54 1 and just from the perspective of an investigator, you 2 made a comment about that the investigator can provide 3 what's routine or what's standard, but a lot of times 4 investigators are specialized in certain aspects and 5 they may or may not have -- be in an institution that's 6 got a breadth of experience in those, so I think the 7 more guidance you can give, there is a big burden to 8 the investigator as they have to understand more and 9 more about what fulfills regulations and if you were 10 asking where a future part would be that could explode 11 on us, I think we are demanding more and more of 12 investigators that they have to understand more and 13 more complex ethical issues of their research which 14 they may or may not have the training. And they often 15 look to the IRBs to provide that, so it's almost like 16 this back and forth. So the more guidance and 17 standardization with the larger community really will 18 help, I think, for -- especially investigators that may 19 not be at an institution that has this huge industry 20 going. 21 DR. KORNETSKY: Nancy, you bring up a 22 very good point. We've concentrated on the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 55 1 definitions, however, I know that IOM and NHRPAC have 2 spent a lot of time in thinking about sort of expertise 3 that in order to do these and make these determinations 4 one of the biggest protections for children is the 5 expertise at all levels, that the people who are 6 evaluating it, at the investigators. So I think that 7 goes without saying and applies to many things, even 8 outside of the definitions. 9 CHAIRMAN PRENTICE: Mary? 10 DR. POLAN: I just wanted to extend that 11 a little bit. I was thinking about in the same line as 12 Nancy and taking it one step farther. Perhaps the most 13 important protection for children are their parents or 14 their guardians. So have you all talked about how -- 15 it's important that investigators understand this and 16 that PIs understand it and IRBs understand it. But it 17 also needs to be communicated to the parents. And have 18 you all talked in your Committee about how you are 19 going to get parents to understand this who are 20 actually going to be the ones to sign informed consent 21 for their children? 22 DR. FISHER: The way that -- first of NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 56 1 all, we haven't as of yet. The IOM report does address 2 this, but in a separate section on how to facilitate 3 parental permission and child assent. 4 What I would say, however, is that and 5 having been -- some of us are also on the IOM 6 Committee, Susan, Susan and myself, is that we look at 7 the assessment of risk process in some sense like a 8 Russian doll in the sense that an IRB has to determine 9 that the risks and benefits of a research study are 10 fair and balanced and ethical for any parent or child 11 to participate in. 12 So that's why it's a protection because 13 the parent can't know everything. Then, there has to 14 be adequate parental permission and child assent 15 procedures so that a parent can decide whether or not a 16 study that's considered ethical is appropriate for his 17 or her child. So that's why that would be the second 18 set. 19 DR. KORNETSKY: This is really the first 20 level of protection, the IRB. And then whether a 21 parent needs to understand sort of all the intricacies 22 here of these things, I think once the IRB comes out NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 57 1 with a determination, that is a reasonable thing for 2 that particular population to ask, then the protections 3 and I think you're absolutely correct. It's not 4 something that our Committee has dealt with on our 5 docket yet, but the whole issue of parental permission 6 and the child involvement and assent, could, may be 7 something that we could get involved with more deeply 8 in the future. 9 DR. POLAN: I guess I would like to push 10 this one step farther because I don't know the answer 11 to this. Whose responsibility is it to inform the 12 parents? Is it OHRP's or the IRB or the PI? 13 DR. FISHER: It's the PI. 14 DR. POLAN: So it rests completely with 15 the PI? 16 DR. FISHER: Let me just say the 17 procedure is is that the investigator submits their 18 informed consent to the IRB. The IRB approves or makes 19 recommendations for how to make this a better document 20 that's more informative and follows all of the ethical 21 procedures, but then it's the research team that 22 conducts the informed consent interview or the informed NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 58 1 consent procedures. 2 CHAIRMAN PRENTICE: Susan? 3 DR. WEINER: I just want to emphasize in 4 this whole process, of course, there is an important 5 responsibility on the part of the public member of the 6 IRB to make that proxy judgment and of course, it's the 7 individual responsibility of each consent signing 8 parent, permission actually, signing parent. But 9 there's every reason to emphasize the need for active, 10 informed public members and IRBs to help with this 11 process. 12 CHAIRMAN PRENTICE: Nigel? 13 DR. HARRIS: I am looking at the 14 equivalence of well child equivalence and thinking to 15 myself whether or not there are qualifiers involved 16 there. As a child who hated to go to the doctor, you 17 know, I'm thinking that even that requires a good 18 degree of restraint sometimes, even coercion for 19 something like that. 20 As I was barrelling down some of the 21 things that were involved in a well child visit are 22 akin to taking of blood which is something I hate to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 59 1 this day. And you know, so there are even elements in 2 that that to me are not -- that could really harm and 3 the potential -- and the question is whether or not 4 there should be a qualifier or something. 5 DR. KORNETSKY: I think about this all 6 the time because the IRB has the task of sort of 7 looking at the protocol in general. And so I think 8 that they can come up with some type of determination 9 in general, this seems to be something that would be 10 equivalent. 11 But then you have each individual 12 research subject and each individual situation and my 13 own feeling on that is yes, the IRB may make a 14 determination, this is minimal risk for people -- for 15 children at this age, in general, however there may be 16 a specific child that you have to strap down to get 17 blood, you know, and for that individual it may not be 18 minimal risk. 19 I think that investigators and there has 20 to be education of investigators that even though the 21 IRB has made that determination that each individual 22 subject in some way, you need to think about that. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 60 1 DR. FISHER: I think it is very important 2 to underscore that parental permission or adult consent 3 is not a substitute for the IRB's fiduciary 4 responsibility to determine whether or not a procedure, 5 a group of procedures a minimal risk. So you know, I 6 would just in terms of terminology, I would just 7 disagree with Susan a little bit for the nonvulnerable 8 child. I would not say that a blood draw or a pin 9 prick, if, in fact, it's decided that the IRB has said 10 that this is minimal risk for a child that doesn't have 11 a disorder that would make it more, then it's a choice 12 on the part of the parent of the child knowing how 13 children react to something, not to participate, but 14 the risks should still be the same for that normal, 15 healthy child. In other words, I wouldn't call not 16 wanting to be in the study pushing something up to 17 minimal risk or not liking a pinprick pushing it up to 18 more than minimal risk, but rather it's a decision that 19 I don't want this level of discomfort even though it is 20 minimal risk. And that's an important distinction. 21 DR. KORNETSKY: I can agree with that. 22 (Laughter.) NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 61 1 CHAIRMAN PRENTICE: You know, we've 2 utilized a uniform standard of minimal risk for a long 3 time. We didn't call it uniform. We called it 4 absolute. I like the term "uniform." And when we 5 encounter research protocols that have no prospect of 6 direct subject benefit, we either have to find that it 7 fits 404 or we have to find that it's going to meet the 8 requirements of 406. 9 I suspect that there are many IRBs out 10 there that are unaware of this debate that probably 11 utilize a relative standard of minimal risk and if they 12 get educated and I'm certainly endorsing a uniform 13 standard, if they become educated I suspect that this 14 will kick a lot of research protocols into a 406 15 consideration. 16 I also suspect and correct me if I'm 17 wrong, but I think that there are going to be research 18 protocols that cannot meet the 406 requirement unless 19 the requirements are massaged to allow the protocol to 20 meet those requirements and certainly we try to do that 21 in the past when we thought a study was well designed 22 scientifically. We thought it was ethical. It's just NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 62 1 that it just didn't meet the requirements of 406. 2 So I'm wondering what your thoughts on 3 that. The implications of the uniform standard of 4 minimal risk in terms of pushing things into 406 and 5 maybe out of 406 into 407? 6 DR. FISHER: Well, I don't think the 7 definition of minimal risk will push things into 407 8 from 406 and I think you'll see 406 has its own 9 problems. 10 CHAIRMAN PRENTICE: If it can't get 11 through 406, then it will get kicked into 407. 12 DR. FISHER: Right, but irrespective, I 13 don't think it's the -- as we'll see when we get to the 14 406 language, I don't think it's the minimal risk that 15 would begin to push things into the 407. It's all the 16 other terms that are utilized. 17 But I would hope that in OHRP issuing 18 greater guidance if a uniform standard is adopted that 19 it would appropriately push certain IRB decisions into 20 the 406, but also it would facilitate some expedited 21 review because it would also be clear what is minimal 22 risk. Right now it's not clear either way and I think NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 63 1 sometimes for a 404, for a minimal risk people are 2 applying the 406 criteria because they don't know what 3 else to do, given it's a relative standard. 4 And so my hope would be that it would 5 even out, that in fact, there would be somewhat greater 6 continuity in how IRBs approach this and those that are 7 truly minimal risk are not going to go through all the 8 kind of obstacles that some of the researchers had to 9 go through, especially social behavioral research to 10 either be expedited or go through as minimal risk. So 11 I would hope it would balance out. I agree with you 12 more will be put in -- others will be put into 406. 13 CHAIRMAN PRENTICE: You've been thinking 14 an awful lot about minimal risk, obviously. You've 15 analyzed their history of minimal risk. I'm curious as 16 to what you think about the standard of minimal risk 17 applied to research involving adults. It's wishy-washy 18 in the regulations. It's interpreted either way by 19 IRBs. Do you think that in research involved in adults 20 it ought to be a uniform standard or a relative 21 standard? 22 DR. FISHER: Well, my expertise is more NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 64 1 with children than adults, but the distinction that we 2 were making on why children would need added 3 protections for minimal risk definition is that in most 4 instances they do not have the legal right, the 5 cognitive ability or the experiential decision making 6 track record or authority to make those decisions. So 7 that one of the protections for a relative standard 8 with adults is good informed consent. But for 9 children, a third party is basically making this 10 decision to involve them in what might be called 11 minimal risk. 12 So I have less problems with the relative 13 definition for adults with appropriate informed consent 14 and if they are adults with the cognitive capacity to 15 consent. 16 So I mean -- in thinking about it and I 17 haven't thought through all the different examples of 18 adult research, but I think there is an argument to be 19 made that irrespective of which criteria is used for 20 adults, children do require this added protection of a 21 conservative approach to minimal risk. 22 DR. KORNETSKY: Ernie, I really haven't NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 65 1 thought about it. I'm sort of looking at that list and 2 saying okay, would this be a reasonable list for 3 adults. I haven't given enough thought about it. 4 I do think you bring up sort of the issue 5 of inconsistencies in definitions in the different, in 6 the regulations, Subpart A and B and C. And that could 7 be problematic, at least from OHRP's standpoint, but I 8 agree with Celia, for children, because of their 9 vulnerability, I think that's the greatest argument for 10 moving this, but I really haven't thought about it for 11 adults. 12 CHAIRMAN PRENTICE: Mark? I'm sorry, 13 Tom? Tom, then Mark, then Felix. 14 MR. ADAMS: The Subcommittee is 15 indicating that minimal risks should be age indexed and 16 certainly is reasonable in and of itself. The question 17 would be do you anticipate developing guidelines as to 18 what the different levels of risk should be at 19 different ages in the different classifications of 20 research? 21 DR. KORNETSKY: I think you are coming 22 back to expertise again. If you have people on an IRB, NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 66 1 if you're evaluating pediatric research, if you have a 2 pediatrician, you'll know that having a child undress 3 when they're a four year old versus when they're 13 4 years old is different. So we haven't given thought to 5 that, but I think it comes back to expertise and there 6 are so many different things, I mean child 7 developmental specialists types of questions. I'm not 8 so sure that we could come up with an exhaustive list. 9 We may be able to give some examples as we have for 10 educational purposes. 11 DR. FISHER: I also think that there is 12 an optimal balance between providing too much detail 13 because when we provide too much detail, anything that 14 doesn't fit in -- it precludes IRB decision making, at 15 the same time with no kind of examples, then you're 16 leaving the IRB to itself. So I don't -- we want to 17 have case examples, but we also want to make it clear 18 that this is a way of thinking. It's a way of making a 19 decision. It is not the decision for the IRB. 20 CHAIRMAN PRENTICE: Mark? 21 MR. BARNES: I just want to go back to 22 this issue of the definition of minimal risk and the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 67 1 normal versus the outlier. 2 One odd thing about this and I just want 3 to point this out in anticipation of Subpart C 4 presentation this afternoon is that since we have in 5 Subpart C a comparator that is put into the text which 6 says that a healthy person is the comparator, that 7 would lead one in looking at the whole -- all the 8 subparts in context, the conclusion that the comparator 9 in Subpart A is not the healthy adult, but instead 10 that's a relative standard and that's not to say that 11 it would be therefore unwise or impossible to impute 12 different considerations in applying the minimal risk 13 definition to the subpart that you have dealt with, but 14 it is to say that I think the presence of the 15 specificity of a healthy person as the comparator in 16 Subpart C would lead to the conclusion that the 17 comparator in Subpart A's definition really is a 18 relative comparator. 19 CHAIRMAN PRENTICE: Good. Mark, can I 20 ask a clarification? What about Subpart B? That's the 21 only other additional subpart that mentions minimal 22 risk as one of the threshold criteria for determining NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 68 1 additional protections. 2 MR. BARNES: That I don't know, Ernie. I 3 hadn't really thought about that. I'd have to sort of 4 sit down and puzzle over that before I could say 5 anything about it. 6 CHAIRMAN PRENTICE: Why don't you puzzle 7 over that between now and tomorrow morning. 8 (Laughter.) 9 MR. BARNES: I take that as my homework 10 assignment. 11 CHAIRMAN PRENTICE: Felix? 12 DR. GYI: As I sit here and listen to the 13 discussion and hear the number of times we put the 14 gatekeeping activity on the IRB, I see that we all 15 recognize that there's a great level of 16 misunderstanding that exists on the IRB side, on the 17 investigator side, on the public side so there has to 18 be a great deal of education that has to be done across 19 the board to help just digest where we want the 20 definition thresholds to be. 21 Even as we sit here though, Susan raised 22 the issue that we ought to remember that certain NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 69 1 procedures have to be looked at in light of its 2 relative risk as opposed to the entire research. 3 That's what I heard you say so far. If I heard you 4 wrong, please correct me, but there has to be some 5 evaluation of that procedure and make a determination 6 and then apply that again on another level to the 7 research project itself. 8 DR. WEINER: No, that is not quite what 9 I said. I said that the procedures have to be 10 evaluated independently of the entire protocol. You 11 can't consider a procedure, yeah, that the judgment is 12 not, the judgment of that minimal risk is not to be 13 made globally of the entire protocol if it has separate 14 procedural research components. 15 CHAIRMAN PRENTICE: That is called a 16 component analysis of risk and you look at every single 17 research intervention and you have to classify it as. 18 Let's say you've got five interventions. Four are 19 clearly minimal risk, one is more than minimal risk. 20 You're automatically out of the 404. All right, if 21 there is no benefit you're automatically out of the 405 22 and you get kicked into the 406. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 70 1 And the Subcommittee, I assume, will get 2 into this component analysis of risks and benefits 3 which is extremely important in determining whether or 4 not something would qualify as a 405 or a 406. 5 DR. GYI: Thanks for that clarification 6 because it leads up to the point I wanted to make which 7 is availability of guidance that helps IRBs make those 8 types of determinations as well as education of 9 external agencies like the accreditation agencies that 10 retrospectively look at how an IRB has behaved and the 11 standard operating procedures and written procedures 12 are in place. And currently, there aren't, there isn't 13 a lot of guidance, so IRBs are in safe harbor in 14 certain cases in making determinations in the way that 15 they did at that time. 16 So I would ask that just as a cautionary 17 statement, perhaps back to OHRP that we have better 18 granularity to help in the documentation processes. 19 DR. FISHER: Ernie, if you don't mind, 20 I'd really like to get the Committee's kind of feedback 21 on whether the direction we're going is correct. 22 Because remember, in order for the Subcommittee to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 71 1 start talking about 406, we need to get a sense of, 2 especially whether we're talking about a uniform or a 3 relative definition. And so any thoughts that the 4 Committee has without approving the proposals as a 5 specific recommendation, but you know, where you're at 6 in your thinking about is this pretty much with fine 7 tuning of language and some weak or strong parts, where 8 you think 404 should be going or is it not? Because 9 that's critical for us to know at this point. 10 CHAIRMAN PRENTICE: Also, I would like to 11 see us actually, if we choose to endorse the uniform 12 standard of minimal risk as a preliminary proposal or 13 as a proposal, not even a preliminary proposal, as a 14 proposal. It's not a recommendation yet. It's still a 15 proposal. So that we have accomplished something today 16 when we say that we've accepted this at last in a 17 preliminary sense and then we can go on and look at the 18 other areas. 19 DR. KORNETSKY: I think that's important 20 for the work of the Subcommittee. If we did have some 21 type of endorsement that this seems to sum it up. It 22 would be helpful because as you will see it only NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 72 1 becomes a lot more complicated from here. 2 CHAIRMAN PRENTICE: Mark? 3 MR. BARNES: I'm tempted to make a motion 4 that we do that, but I really want to hear how 406 fits 5 in before we make any motion. I want to understand 6 what the next step of this is, so that we can 7 understand whether the first step is wise or not. 8 DR. FISHER: Sure, that's fine. I also 9 wanted to underscore that all of the Committees that 10 have reviewed children's, even back to the National 11 Commission, have always suggested the uniform standard. 12 I don't know what went on in 1981 or 1983 or whichever 13 year it is, but you know the National Commission on 14 Children recommended the healthy standard. NHRPAC 15 recommended it. The IOM recommended it. So there is a 16 history to it. We're not inventing the wheel here, but 17 there has been a 30-year history, actually, of thinking 18 that this would be appropriate for children as a 19 vulnerable population. 20 CHAIRMAN PRENTICE: I think the story and 21 this is anecdotal, I don't know if it's true or not, 22 but the story is that the framers of Subpart D were NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 73 1 carrying out a debate about whether or not it ought to 2 be a relative standard or uniform standard and they 3 were getting up to the wire, the ninth hour. And they 4 finally decided that they could not make a decision so 5 they didn't make a decision and that's how it got 6 kicked back to the definition that's in Subpart A. 7 DR. KORNETSKY: I have been told the same 8 story by one of the people who was involved. 9 CHAIRMAN PRENTICE: So let's hope that we 10 can make a decision. 11 DR. JONES: I just have a question too, 12 on this minimum standard, how does it apply when there 13 is a benefit? Is it the same definition? 14 DR. FISHER: The way, interestingly -- 15 first of all, if there is direct benefit to the 16 procedure, then it's under 405. Now there may be 17 intervention studies to which some of the research 18 procedures are of direct benefit but others are not and 19 so once again here's this component analysis that it's 20 not the entire research in and of itself when added up, 21 but rather whether the types of procedures that are not 22 of direct benefit, but are there to collect the data on NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 74 1 the direct benefit procedures, they have to be 2 evaluated as -- 3 DR. JONES: I guess what I'm asking is 4 then would this standard for minimal risk hold across 5 the different -- 6 DR. KORNETSKY: Yes, absolutely. 7 DR. FISHER: 405 doesn't ask -- 405 8 doesn't use the term. 9 The only direct benefit classification 10 there is is 405 and it does not use the term minimal 11 risk. So there is not a ceiling, there is not a 12 restriction on the amount of risk when there is direct 13 benefit involved. Then you have to do the calculation. 14 Is the direct benefit -- are there greater than 15 minimal risks? If there are then balanced by the 16 potential direct benefit to the child. 17 DR. HARRIS: I have a procedural 18 question. If we said yes, you know, you're headed in 19 the right direction, can you just say quickly how are 20 we going to move forward? I mean what does that yes 21 mean? 22 DR. FISHER: I think Mark made a very NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 75 1 good point that I think you'll see some of what the yes 2 means when we talk about 406. I think the yes would 3 mean -- once we get -- all those 11 proposals are based 4 on a uniform standard. If, in fact, there's a 5 preference for relative standard, we really have to go 6 back. We won't have a history, a Committee history, 7 IOM, NHRPAC, we don't have a written rationale for 8 using a relative standard for children. 9 And so we would really have to think 10 through what would be the guidance for IRBs if, in 11 fact, they're supposed to use a relative standard. 12 Once you see 406, I find it difficult to understand how 13 they wouldn't be applying the criteria 406 to examine, 14 to utilize a relative definition in 404 and therefore 15 we would have two redundant types of classifications. 16 So I think there is research that is 17 minimal risk for everyone, except for those kids who 18 might be more vulnerable to it and that therefore it 19 would expedite in not only the formal way, but in the 20 overall way the review process for IRBs. So we just 21 say okay, that's minimal risk and we're moving on from 22 here. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 76 1 DR. KORNETSKY: Nigel, I think what 2 you're asking, if that's sort of endorsed today and we 3 bring it back to the Committee, first of all, you'll 4 see how this will serve for a basis for our future 5 deliberations. I think the hope is that we would come 6 back to you as -- to come back with sort of a whole 7 package of many of the other types of things which we 8 would then ask for recommendations, full endorsement, 9 that would then go as a letter to the Secretary, that 10 then would be interpreted by OHRP for guidance. I mean 11 the end result is guidance. There is a light at the 12 end of the tunnel. 13 DR. FISHER: But also, before we present 14 the 406, if there are other aspects of the presentation 15 that bothered you, we need to know. We haven't spoken 16 about -- maybe they didn't. I don't know, but in terms 17 of I think Nigel, you raised some very good points 18 about the well child visit. If there are others about 19 the psychological test equivalent or the exception to 20 these. If there's anything and you might want to get 21 back to it after 406, but I don't want to stifle, I 22 just want to remind you if anything else in the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 77 1 presentation elicited some kind of reaction. 2 CHAIRMAN PRENTICE: Tom? 3 MR. ADAMS: Just a quick question, did 4 the Committee in terms of developing these different 5 points look at others and discard them? 6 DR. FISHER: I think we did, but they 7 weren't stated as here's a proposal and we're going to 8 discard this. 9 DR. KORNETSKY: I don't remember anything 10 -- I think in some of the other -- it wasn't that it 11 was discarded in some of the other discussions. There 12 still is and I think the presentation Celia will point 13 out where we still have some disagreements in some of 14 the others. On these, I can't -- 15 DR. FISHER: Well, for example, I guess 16 we just take it for granted because the discussion is 17 do we accept the negative and so let me give you an 18 example of equivalence. Equivalence, the alternative 19 proposal is no, it is only those exact procedures that 20 are in a well child visit. That's the alternative 21 proposal to the equivalence. 22 The equivalence is no, it doesn't have to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 78 1 be the exact procedures, but you need to use the well 2 child visit as a reference point for magnitude and 3 probability of harm. So basically we did very 4 carefully look at the alternative for all of these, but 5 they weren't stated as a proposal. 6 DR. WEINER: This is a synthesis of 7 discussions where each one of these emerged as an idea 8 that was relevant to this definition. And so it wasn't 9 as if this was the list that we considered first. 10 DR. FISHER: Right. It's inductive. So 11 the sequential and organized session in which all of 12 this was presented was really the result of trying to 13 grapple with how all these points are interrelated in 14 what's going on. 15 CHAIRMAN PRENTICE: I think I would like 16 to respond one of Nigel's questions earlier. I really 17 believe that the ethical and regulatory based integrity 18 of Subpart D is totally dependent upon how you define 19 minimal risk. That's the first step and everything 20 else needs to fall into place in accordance with the 21 definition that we ultimately adopt. That's so 22 important and we've not had a consensus on how we NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 79 1 should interpret minimal risk ever. And that's why we 2 need to have one. And the work of his Committee is 3 very, very important. It has implications for Subpart 4 C, Subpart B. It even has implications for Subpart A 5 to some extent. 6 What I would like to suggest is that we 7 not go into your next presentation and that we take a 8 break because we're always over in our break time 9 anyways. So we will reconvene at 10:45 with the second 10 half of your presentation. 11 Also, remember to fill out your lunch 12 requests, if you would. 13 (Whereupon, the foregoing matter went off 14 the record at 10:18 a.m., and went back on the record 15 at 10:52 a.m.) 16 CHAIRMAN PRENTICE: All right, we're going 17 to continue our discussion of the Subpart D issues that 18 Celia and Susan have raised. So, Celia, would you 19 please take over? 20 DR. FISHER: Yes. All right. And now we 21 get to the harder part. This was relatively 22 straightforward, but when we get to 406, we have some NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701www.nealrgross.com 80 1 additional problems and challenges. 2 So, just to remind you, 406 starts out 3 with, DHHS will conduct or fund research. Now just to 4 remind people that 404 is, doesn't have to have any 5 direct benefit but be of minimal risk. 405 is 6 intervention. 7 There is no ceiling on risk there. Okay. 8 So now we're in 406 that goes back to no benefit but 9 can be greater than minimal risk. Okay? So that's 10 what we're talking about. 11 So here you can see then minimal, in 12 which the IRB finds that more than minimal risk to 13 children is presented by an intervention or procedure 14 that does not hold out prospect of direct benefit for 15 the individual subject, or by a monitoring procedure 16 which is not likely to contribute to the well being of 17 this subject only. 18 So here, because it's going to be gr