UNITED STATES OF AMERICA DEPARTMENT OF HEALTH AND HUMAN SERVICES SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTIONS INAUGURAL MEETING TUESDAY JULY 22, 2003 + + + + + The meeting was held at 8:30 a.m. in the Room 800 of the Hubert Humphrey Building, 200 Independence Avenue, S.W., Washington, D.C., Dr. Ernest Prentice, Chairman, presiding. PRESENT: ERNEST D. PRENTICE, Ph.D. Chairman THOMAS L. ADAMS, CAE Member MARK BARNES, J.D., LL.M Member CELIA B. FISHER, Ph.D. Member E. NIGEL HARRIS, M.Phil., M.D., D.M. Member ROBERT G. HAUSER, M.D., FACC Member NANCY L. JONES, Ph.D. Member FELIX A. KHIN-MAUNG-GYI, Pharm.D., M.B.A., CIP Member SUSAN KORNETSKY, M.P.H. Member MARY L. POLAN, M.D., Ph.D., M.P.H. Member SUSAN L. WEINER, Ph.D. Member BERNARD A. SCHWETZ, D.V.M., Ph.D. Ex. Secretary EX OFFICIO MEMBERS PRESENT: LYNN CATES Veterans Administration SALLY FLANZER Agy. for Healthcare (for Francis Chesley) Research and Quality EX OFFICIO MEMBERS PRESENT: (cont.) CHRISTINE GRADY National Institutes of Health (for Lana Skirboll) DAVID A. LEPAY Food & Drug Administration DEBORAH A. PRICE Dept. of Education PETER W. PREUSS Environmental Protection Agy. PHILIP RUBIN National Science Foundation TRYN STIMART Dept. of Commerce (for Linda Beth Schilling) ALSO PRESENT: TOMMY THOMPSON Sec., DHHS RICHARD H. CARMONA, M.D., M.P.H., FACS Surgeon Gen. AGENDA ITEM PAGE OPENING REMARKS: Bernard Schwetz 5 COMMITTEE INTRODUCTIONS: Ernest Prentice 11 REVIEW NHRPAC UNCOMPLETED ACTIVITIES: Ernest Prentice 18 Questions/Comments: 31 Subpart C: Karena Cooper 39 Questions/Comments: 54 Subpart D: Ernest Prentice 58 Questions/Comments: 76 ADMINISTER OATH/GIVE CHARGE TO SACHRP MEMBERS: Honorable Tommy G. Thompson 110 SACHRP PRIORITY SETTING DISCUSSION: Option of Creating Subcommittees of SACHRP: Ernest Prentice 120 Questions/Comments: 122 Advise HHS on Responsible Conduct of Research Involving Special Populations: Ernest Prentice 134 Questions/Comments: 138 Action Taken on Motion: 152 Advise HHS Relative to Accreditation of Human Research Protection Programs: Ernest Prentice 152 AGENDA ITEM PAGE Questions/Comments: 155 Action Taken on Motion: 204 Adverse Event Reporting Requirements and Role of DSMBS Discussion: 204 Action on Motion: 236 CLOSING: Ernest Prentice 238 P-R-O-C-E-E-D-I-N-G-S 8:41 a.m. EX. SECRETARY SCHWETZ: Okay. Let's start again. Good morning to all of you. Now that we have the microphones working, we still don't have the ability to use PowerPoint, so we're not fully ready to go yet. That's what we are waiting for for a minute. We will proceed and hope that the rest of the capability will be hooked up soon. There was also a problem in that we had a lot of these books that were ready for people and when they were delivered yesterday, the person who should have been here to receive them and keep them here wasn't, so they went back to some place in a remote location and they are being retrieved this morning. So we'll have more of these shortly. Beyond that, let me be the first one to invite all of you formally or not invite, but thank all of you, to welcome everyone to this 1st meeting of the Secretary's Advisory Committee. It has been a long time in the planning and getting everybody confirmed and getting everything together. But I'm glad that we are here for this 1st meeting today. I certainly want to thank all of the Committee members for agreeing to help us in this important task, and I would also, in particular, want to give special thanks to Dr. Prentice for agreeing to chair this Advisory Committee. A lot of you have known each other as people in the field that you are part of for some time, and that gives us an advantage in moving the dynamics forward that you know each other. And in addition, I'm sure all of you are familiar with the predecessor committee NHRPAC. But, in fact, this is a new Committee. There are many of the same issues that we would want to consider, but we're under new leadership in several different ways. Dr. Prentice as the new Committee Chair for this activity, me as the acting head of OHRP, at least on an acting basis, but I represent some new thoughts, new leadership, new perspective, and compared to the time when NHRPAC was formed, Secretary Thompson is new to this scene. So there are a lot of things that are different than when NHRPAC started, and not to say that we're going to work on entirely different things or that the objectives or the procedure would be different, but one thing that we want to talk about today are some of the things that were left over from NHRPAC and not that that's what your agenda has to be, but we wanted to start there and see if there are things that we needed to take to completion, as well as look at other agenda items. So there are some expectations that we have in terms of what we would like to get done today. One thing is to identify what some of the priority issues are for the Advisory Committee to work on for the next couple of years. So the highest priority issues and also some back burner kinds of issues that may well become high priority issues as we work. So we want to know for sure what are the most important tasks that this group will take on. But have in mind a list of other agenda items beyond that that may or may not surface as a high priority during the time that we work. Recognizing also that there probably will be other issues that compete with whatever we identify in this 1st meeting or two, and that we would want to be able to deal with issues as they come up. So one of the things that we also want to talk about today is the process of having subcommittees to the Committee. There are some activities that we would like to move up to have them more transparent. In particular, the review of protocols for studies in children where we have been doing that, rather than hold them up, but it has been on an informal basis and it hasn't been as transparent as we would like to have it. So one of the issues that we're going to talk about is having subcommittees of this Advisory Committee that would have one or two members from the Advisory Committee and other experts selected to do certain review activities and then report back to the Advisory Committee. We'll go into more detail in that after a bit. So another thing that will happen today is Secretary Thompson is scheduled to be here at 11:30 and say a few words and swear everybody in and answer questions if you have questions of him. Another thing that I'm hoping we will have a chance to talk about today is logistics for future meetings. And it isn't a given that we'll have future meetings here. We're more likely not to. But it was convenient to have this 1st meeting here today and have the Secretary come in and some other people from the Department be able to come in easily during the day. But we would kind of like to have your recommendations on where would be good places to meet, because there are hotels all over, and whether you stay downtown or you go out in some other area, those are things that we have some flexibility, but I would like to be in the process of defining the calendar for the next couple of years, so that we have some dates that we have at least tentatively on our calendars and that we, in the first meeting or two, have some agenda items that we would agree upon. I also need to keep in mind that the Advisory Committee is advisory beyond OHRP. It would be easy for me to think that this is an Advisory Committee to our office, but, in fact, it isn't. It's advisory to the Department, advisory to the Secretary, and to that end, I also want to thank the ex officio members, who are here, because whether it is within the Department, the various agencies within HHS or the other 16 departments outside of HHS that come under the common rule, this group can be advisory to all of these agencies and departments. Because one of the things that I have learned as I've gone through this in the last few months, since coming to OHRP, is that it isn't very often that one of the agencies has an issue that isn't important to other agencies as well. So I look forward to working more closely with all of the ex officio members as well. While you are non-voting members, I'm hoping that you will be a resource for the official members of the Advisory Committee and that you will weigh in on priorities and other things as the agenda items come up. So I would encourage you Committee members to think of the ex officio members as a resource to you to provide information on how things go in other agencies, either within HHS or outside of HHS. Just a couple of housekeeping things and then I'll turn it over to the Chair. One is that you can't see it, it's well-hidden up here behind the screen, but for the Committee members there's coffee and water and juice and some small things to eat, so help yourselves as we go. Bathrooms are down the hallway to the left across from the entrance into the cafeteria. And whether or not there is a break is up to the Chair. So that's his call. Other than that, I think I will close by introducing Dr. Ernie Prentice, the associate vice chancellor for Academic Affairs and Regulatory Compliance, an associate dean for research, Nebraska Medical Center, Omaha, and Chair of this Committee. Ernie, I'm very pleased to be able to work with you. CHAIR PRENTICE: It took a while to get the Committee started. The confirmations took some time. I'm still not confirmed that's why I have a hand-written name tag. I would like to add my welcome to that of Dr. Schwetz and good morning, everybody, good morning, members of SACHRP, ex officio members, representatives from other Government agencies, and most importantly representatives from the public, who have an interest in protection of human subjects. As Dr. Schwetz mentioned, we have PowerPoint, but right now we don't have that capability. Perhaps that's good, because I have 50 presentations on my computer, enough to last for three days. So maybe without the advantage of slides, I might be a little bit more brief and save you from that. We have an ambitious agenda today. For those of you who have access to the books, we're going to be talking about a lot of issues. But I want to begin with a public acknowledgement of the work of NHRPAC. NHRPAC, as you know, is the National Human Research Protections Advisory Committee, chartered by Donna Shalala back in 1999, and they worked very hard, tirelessly and produced a series of excellent reports, reports on research involving children, reports on research involving decisionally impaired, etcetera. This Committee is going to take up where NHRPAC left off. We will utilize the good work of NHRPAC as kind of a platform where we can pursue the agenda of SACHRP as set forth by Secretary Thompson. I want to recognize the fact that NHRPAC was under the leadership of Dr. Mary Faith Marshall and I'm very pleased to note that we have two members of NHRPAC who have agreed to continue serving on SACHRP, and those members are Mr. Mark Barnes, the gentleman over here, and Ms. Susan Kornetsky, the young lady right over there second from the end. So thank you for agreeing to continue and we're going to take advantage of your wisdom and your expertise and your experience. And now it is my pleasure to ask each of the SACHRP members to introduce themselves, beginning with Dr. Harris. Simply tell us who you are and what you do and dispense with, you know, a light history if you would. COURT REPORTER: We can't hear you. DR. HARRIS: Okay. I'll keep it down. There we are. I'll start again. I'm E. Nigel Harris. I'm dean and senior vice president for Academic Affairs of the Morehouse School of Medicine in Atlanta. I'm a rheumatologist by training and spent most of my career in academic medicine and a lot of that doing both bench and clinical research studies. DR. FISHER: I'm Celia Fisher. I'm the director of the Fordham University Center for Ethics Education. I also hold the Marie Doty University Chair in psychology. I'm a psychologist and do research on research ethics. BOARD MEMBER ADAMS: Thank you, Celia. I'm Thomas Adams, the executive vice president and chief executive officer for the Association of Clinical Research Professionals in Alexandria, Virginia. We are an individual membership organization comprised of about 18,000 clinical research professionals worldwide. DR. WEINER: I'm Susan Weiner. I'm a patient advocate in childhood cancer. I head a group called the Children's Cause. In my former life, I was a developmental psychologist, who was a researcher and was a parent of a child with cancer who lived for nearly 14 years. BOARD MEMBER BARNES: Good morning, I'm a partner at a large law firm called Ropes and Gray, and I represent a number of both IRBs and academic medical institutions on the one hand and matters involving clinical research, and on the other, pharmaceutical companies and medical device companies in their clinical research activities. I'm a former public health official at the local and state level in New York State and City, and a former AIDS advocate, patient advocate for people with AIDS when I was a law professor at Columbia University in New York. DR. HAUSER: I'm Bob Hauser. I'm president of the Minneapolis Heart Institute in Minneapolis. I'm a general cardiologist. My research interest is in the field of medical devices, particularly the safety of pacemakers and implantable defibrillators. DR. JONES: I'm Nancy Jones and I'm at Wake Forest University School of Medicine. There I'm a basic researcher as well as interested in ethics, in particular, at the interface between the bench and human subject research. DR. GYI: Good morning. My name is Felix Khin-Maung-Gyi. I'm the founder and chief executive officer of Chesapeake Research Review. It's a company that provides for human subject protection by offering services and consulting education and independent IRB services focused on human research protections. I'm also a senior policy fellow at the University of Maryland Center for Drugs and Public Policy. BOARD MEMBER KORNETSKY: Good morning. I'm Susan Kornetsky. I'm director of Clinical Research Compliance at Children's Hospital in Boston, and I've been working full-time with IRBs for the last 20 years. DR. POLAN: Good morning. I'm Mary Lake Polan. I'm professor and chair of the Department of Obstetrics and Gynecology at Stanford University. I'm a reproductive endocrinologist for the clinical practice. I have a research laboratory and a recent interest in international public health. CHAIR PRENTICE: Okay. Thank you. I'm very pleased to have the opportunity to work with such a prestigious experienced Committee. And now I would like to invite the ex officio members of SACHRP to tell us who they are or who they are representing and their agency. DR. LEPAY: I'm David Lepay. I'm senior advisor for Clinical Science and director of good clinical practice programs at the U.S. Food and Drug Administration. MR. STIMART: Good morning. I'm Tryn Stimart, the human and animal subjects advisor to the Advanced Technology Program with the Department of Commerce. MS. PRICE: I'm Debbie Price. I am the chief of staff at the Office of Federal Student Aid in the Department of Education, and I'm the Secretary's representative. DR. RUBIN: I'm Philip Rubin, the director of the Division of Behavioral and Cognitive Sciences at the National Science Foundation and co-chair of the NSTC Human Subjects Research Subcommittee. MS. GRADY: I'm Christine Grady from the National Institute of Health, but I'm here in lieu of Lana Skirboll, who is the chief of the Office of Science Policy at the NIH, who will be the ex officio member. MS. CATES: I'm Lynn Cates. I'm the assistant chief research and development officer at the VA in charge of the program for research integrity. I'm in charge of policy and education in human subjects protection at the VA. MS. FLANZER: I'm Sally Flanzer. I'm here representing Francis Chesley, who is representing AHRQ, the Agency for Health Care Research and Quality. CHAIR PRENTICE: Okay. Thank you. We also have a number of members yet to be appointed, so hopefully by our next meeting the roster of the ex officio members will be complete. Now, on to my PowerPoint. I want to begin with a brief overview of the role of SACHRP, as indicated in the charter, and this will be amplified by Secretary Thompson when he comes in at 11:00 or 11:30. We are charged with advising the Secretary on all matters pertaining to the protection of human subjects. But we've been given a particular emphasis on special populations, populations that are considered to be vulnerable, such as children, neonates, prisoners, the decisionally impaired, embryos and fetuses. We're also charged with providing advice on various issues concerning international studies with research involving identifiable tissue samples, which has become an extremely important issue these days with the kinds of research that is ongoing. We've been asked to provide advice with regard to investigator conflicts of interest, which as you know is something that a number of professional organizations have already issued reports on. And also, we are to advise the Secretary concerning various OHRP activities and planned activities. So today, we're going to be talking about some of those issues and trying to chart a path whereby we can pursue various areas and provide appropriate advice to the Secretary and to OHRP. Now, on January 3, 2003, Secretary Thompson issued a quote in the press release for the appointment of this particular Committee, and I quote, Secretary Thompson said "We must make sure we allow science and medical research to advance for the good of all Americans, but not at the expense of the people who participate in clinical trials." Now, I have not had an opportunity to talk to Secretary Thompson about this, but I suspect that he is reflecting upon the past and thinking about the future of clinical research. And when he reflected upon the past, undoubtedly, he thought about some of the rocky events which have occurred in the area of clinical research, particularly over the last four years. And I have a slide that is titled "Sentinel Events and Agents of Change 1998 to 2002." And I have a series of slides after that that illustrate some of these sentinel events. So without the benefit of the visuals, I'm going to try to create a verbal picture in your mind. I want to go back to 1998. As you perhaps know, the OIG issued its report on IRBs, and it was an indictment of the system. Clearly, there were deficiencies that needed to be corrected. And that OIG report precipitated a series of actions, I think, on the part of OPRR over the next few years beginning with the shutdown of research at Rush-Presbyterian-St. Luke's Medical Center in Chicago, Illinois in October of 1998. Over 1,500 research projects were halted at Rush because of deficiencies in their system for protection of human subjects. This was kind of a shock to the research world. We all took note of what happened at Rush, and I might add that under the leadership of David Clark, they have a model system for protection of human subjects there. But back in 1998, they had some problems. The next slide is an interesting collage of newspaper headlines that show a whole series of research shutdowns carried out by OPRR and its successor office OHRP. There is a slide that is titled "U.S. Halts Research at Duke." Duke, the seventh largest funded medical center in the country. This was a real shock. The institution and other institutions came to think, you know, if it could happen at Duke, could it happen here. We began to wake up. There was a shutdown to research at the West LA VA Medical Center. That precipitated an overhaul of the VA system for protection of human subjects and the subsequent establishment of a new office called ORCA. It also launched an accreditation system with the VA hospitals, which in turn resulted in another accrediting body for IRBs called AAHRPP, which we'll talk about this afternoon. The slide shows shutdowns at the University of Texas Medical Branch in Galveston over concerns with regard to research involving prisoners. A shutdown at University of Illinois, Chicago, Colorado University Health Science Center, the University of Oklahoma, Health Science Center in Tulsa, Virginia Commonwealth University, and then, of course, the Hopkins shutdown. In the midst of all this on September 17, 1999, a tragic event occurred in Philadelphia. A young man, 18 years of age, named Jesse Gelsinger, who lived in Tucson, Arizona, went to the University of Pennsylvania to participate in the gene transfer study. He had OTC deficiency, which is a metabolic disorder where he can't process ammonia. Well, Jesse died at the University of Pennsylvania from an overwhelming immunological reaction to the adenovirus vector that was used to transport the gene. And as a consequence of his death, he assumed a new life in a way. He became an agent of change. He brought to the forefront concerns about conflicts of interest. And we've always known about conflicts of interest prior to Jesse, but, quite frankly, no one seemed to pay a great deal of attention to conflict of interest until the tragedy in Philadelphia. And as I indicated earlier, now everybody is talking about what can we do about conflict of interest, and ensure that conflicts on the part of both investigators and institutions do not in any way jeopardize protection of human subjects or introduce bias into science. We had another tragedy that was in Baltimore on June 2, 2001. A young woman named Ellen Roche enrolled in a non-therapeutic research protocol. It was an asthma challenge study involving the administration of an agent called hexamethonium, which is a ganglionic blocker. She suffered from pulmonary toxicity as a consequence of the hexamethonium and she ultimately died. I suspect that Secretary Thompson was thinking about some of these tragic events when he delivered that quote. The next slide is from Time Magazine. It shows a woman in a cage and there is the caption "Human Guinea Pig." Our medical testing has turned millions of, I can't quite read it, into human guinea pigs. Now, think about the power of the media portraying the participation of people in research as human guinea pigs basically the equivalent of, let's say, a laboratory rat. I think that's an unfair, an inaccurate characterization, and that kind of characterization has a detrimental effect on the attitude of people towards participation in clinical trials. And we need to recognize that the advancement of medicine is totally dependent upon the willingness of people to participate in research. All of the benefits that you and I enjoy in our lives, increased longevity, treatment for diseases for conditions that never existed even a few years ago, it's all due to research, which involves both animals and ultimately people. We can't afford to have the public's perception be altered to the point where they distrust the research establishment, they are reluctant to participate in clinical research. They worry about whether or not their rights and welfare come first. So I suspect that Secretary Thompson was thinking about all of these things when he issued that quote and created this Committee. So it's going to be our charge to try to provide advice to the Secretary and to OHRP with regard to how best to protect the rights and welfare of human participants in research and at the same time advance medicine, science and knowledge for the benefit of all of human kind. Now, the next slide goes through the agenda, and you've already heard Dr. Schwetz' opening remarks. You've heard my brief introduction and the charter. We'll be going into an overview of the NHRPAC reports next. We'll talk about unfinished business, because as both Dr. Schwetz and myself indicated, we're going to kind of take up where NHRPAC left off. We have a presentation scheduled at 9:30 on Subpart C, which is additional protection for prisoners. We'll take a break at 10:00, and then we will talk about pediatric research and additional protection for children at 10:15. Secretary Thompson will be coming in shortly thereafter. There will be a lunch break between 12:00 and 1:15, and then the afternoon will be devoted to priority setting discussions, public comments and a wrap-up. Now, for those of you who are familiar with the NHRPAC reports, they developed a report on the interpretations of the additional protections for children, Subpart D, requirements that are in Subpart D, research with decisionally impaired, confidentiality and research data protections, the status of third parties and human subjects as human subjects, human genetics research and they also had a series of comment letters. For example, there was one comment letter that was written to FDA on their version of Subpart D. Obviously, they were unable to finish all of the activities that they had planned. It will be the same with this Committee. There is no way that we can finish all of the activities that we will start. But in terms of some of the unfinished business relative to Subpart D, the additional protections for children, they defined some extremely important terms, such as minimal risk, what constitutes a minor increase over minimal risk, what does it mean when a child has a disorder or condition and what is commensurability? And they had some planned future reports because they recognized the fact that they had not been able to complete their analysis of Subpart D and formulate all of their recommendations. So again, we're going to look at Subpart D from the perspective that we should not under protect our children who participate in research, but neither should we over protect and striking the right balance is the key. And I have a nice slide here showing Baby Fae. Baby Fae, perhaps you remember, had hypoplastic left-heart syndrome. She was dying. At Loma Linda University she received a xenotransplantation involving a heart of a baboon on October 26, 1984. And I simply show that picture to illustrate how vulnerable our children are in research. So OHRP has actually asked NHRPAC for guidance on various aspects of Subpart C next and we're going to look at research involving prisoners as an issue, and what kind of additional protection should exist relative to research involving prisoners. And Ms. Cooper is going to be talking about that in great detail, but I do have a slide that shows the participation of a prisoner at Statesville Penitentiary in Illinois in a malaria experiment. He is actually lying on a bed and there is a jar of mosquitos. The mosquitos are malaria infected and he is being infected with malaria as part of an experiment. And the caption under this particular slide is "Protection of Rights While Restricting Rights is a Question of Justice." Subpart C, additional protections for children, was issued back in 1978. It is now 25 years later. We need to reexamine these regulations and ensure that not only is research conducted with prisoners ethical, it also addresses the issues of justice. NHRPAC produced a report on research with the decisionally impaired. They had some recommendations. They talked about permissible risk levels and appropriate protections and the role of the legally authorized representative, but they recognized the fact that their work was undone. They planned a whole series of future reports on the role of advanced directives, placebo controls, independent capacity assessment and so forth and so on. And the next slide, once again, is designed for impact. It shows a Newsweek cover that is titled "All About Alzheimer's." Perhaps some of you know that back in 1978, additional protections for the decisionally impaired were proposed. It was called Subpart E. However, they were never finalized. This is what I would characterize as a serious regulatory and ethical gap in the regulations that perhaps needs to be addressed. So that's a brief overview of, I guess, why we're here. I think we're at a time of, I wouldn't call it crisis, but I would characterize it as, opportunity. We're at a time when we have the opportunity to advance the field of human subject protection by providing appropriate guidance and recommendations to HHS, which in turn will be considered by OHRP and hopefully within two or three years, we will find that we have a series of reports that are issued by OHRP as guidance for the IRB community and investigators who conduct research with human beings. I can tell you that as a co-chair of an IRB for over 22 years, I have seen a remarkable evolution in the field with human subject protection in terms of our understanding of the ethics and regulation of human subject research, but I can also tell you that there are so many areas that we're desperate for guidance on. And I'm very optimistic that under the leadership of Dr. Schwetz as the acting director of OHRP, I don't know if you plan on continuing on as the director of OHRP, but I know that you have a great staff, I know them all, I have great respect for them, and I'm really looking forward to having the opportunity for SACHRP to work very closely with OHRP in developing the kind of guidance that is needed by IRBs such as mine, and IRBs across the country. So with that as my introduction before I turn the podium over to Ms. Cooper, I would like to invite the members of SACHRP and the ex officio members to ask any questions that they may have at this time. A lawyer is always first. Never reticent to speak. BOARD MEMBER BARNES: That's right. Dr. Prentice, just one thing that I would want to point out. One of the things that NHRPAC did, and actually it was a report that was brought through the complete cycle to final publication, was on the issue of conflicts of interest, both researcher and also institutional conflicts of interest. I think that will be something that is of interest to us today, but I just want to point out that you didn't necessarily mention that in your kind of precis report on or your packet had actually completed. CHAIR PRENTICE: Yes, I apologize for that omission. Once again, it's the fault of the PowerPoint not being up. I was expecting a more vocal group here. Now, you know, as I normally tell my students, if you don't ask me questions, I shall ask you questions. DR. WEINER: I would just like to, you know, as the pediatric patient advocate and family advocate, emphasize for kids with life threatening illness, the question of research is vitally important. And it's very important not to over protect or to under protect. And it's that balance that I hope we can arrive at for deliberations here. CHAIR PRENTICE: Yes, one of the things that I have observed relative to research involving children and the interpretation and application of the regulations by IRBs across the country is it is so inconsistent. And I think that in some cases IRBs are being overly restrictive and they are actually not approving research which should be approved and conducted because it is ethical to do so. On the other hand, there are certainly circumstances where there have been pediatric research projects approved that should never have been approved. And I think we all know about those. So it's important that we be able to issue guidance in terms of how you interpret Subpart D, because that's what an IRB should be using when they review a research project involving children. And if you don't understand how to appropriately interpret the requirements, then obviously you cannot apply them appropriately. And this whole concept of minimal risk, what is minimal risk? Do you utilize an absolute standard based upon the life of a healthy child or do you use a relative standard based upon the life of the individual, research subject who may, in fact, have a terminal illness? There's a distinct difference in terms of the risks of daily life for those two different subjects. So over the years I have found that some IRBs interpret minimal risk utilizing the relative standard and some interpret minimal risk using the absolute standard. NHRPAC has clearly interpreted minimal risk-based upon the life of the healthy child, but that's still not official guidance. That is a report produced by NHRPAC for consideration by the Secretary, but again its not official guidance. There was no requirement for an IRB to apply an absolute standard, so we need to be able to provide official guidance on that particular issue. DR. GYI: Actually, I should be thankful that you didn't have the slides, Dr. Prentice, it gives us an opportunity to ask you some questions. You have mentioned that the media has played a little and detrimental role at times with portrayal of research in a negative light in many cases, such as the Time Magazine article. I'm not entirely convinced that it was received in such a negative way. I think it is good that the media has access to information relating to research that goes on in this country. But there are other issues that impact on how ethical behavior is modulated, and in particular research that tends to result in litigation has a negative impact on all of us, and ability for researchers to behave in a way that is appropriate and ethical, and I hope that as part of the charge of this particular group, we get a chance to address some of these issues and surface some recommendations that we agree are productive for the research community on the IRB, in particular. CHAIR PRENTICE: Thank you, Dr. Gyi. BOARD MEMBER KORNETSKY: I know that we'll get to priority settings, but I just wanted to make a statement that I think it would be very useful for this group to be most effective if there was some priorities that OHRP, Dr. Schwetz and the staff that are here have to help us priortize, and I know we'll get to that in the afternoon, but I think that may be the way to be most useful. BOARD MEMBER ADAMS: Just to follow-up on Felix's remark, I think as we move along, if we could also have some ability to look at the effectiveness of IRBs and what might be done to encourage people to participate more fully with reporting to IRBs, once again, given the liability situation in which they now find themselves. CHAIR PRENTICE: Well, that's an important point, Tom. Once again, I defer to my defunct PowerPoint and I was going to make some remarks about the climate of litigation and the clinical research context that we find ourselves in these days. I guess it started with Jesse Gelsinger and Alan Milstein as, I think, most people know is the attorney of record that sued the University of Pennsylvania and James Wilson and even the ethicist, Art Caplan, at Pennsylvania, and he has since gone on to sue a number of different institutions. Just to name a few, University of Oklahoma Health Science Center. He actually named IRB members in the complaint. The dean, the director of grant contracts, the ethicist who was on the committee was named in the complaint. He has lodged lawsuits against Fred Hutchinson Cancer Research Center, two of them, Ohio State, Oregon. He is involved in the Apgar suit. What we're seeing is a tendency on the part of the plaintiff's lawyers now to name IRB members in complaints, which in turn opens up the entire IRB review process, all of the IRB records, which in turn allows the court to take a look at what the IRB did or did not do, and we found that in the Kennedy Krieger case where the Maryland Court actually decided that the IRB had not reviewed the protocol appropriately and made the appropriate decision. So here we have the court second guessing what IRBs do. If this continues, I suspect that we're going to have a hard time recruiting IRB members who basically are volunteers, don't get paid, usually get lousy lunches at most institutions, who get no credit for the promotion or tenure, and I certainly tell you that is the case at my institution. There is no credit given. I think it is very fortunate that we have such dedicated people, who are prepared to serve under these circumstances, but it's going to become more and more difficult if this continues. And I know that at least two members of the SACHRP committee and Dr. Gyi and Mark Barnes have expressed concern about this particular problem and it's perhaps something that we ought to be looking at as a committee. So that would be relegated to this afternoon. DR. FISHER: Thank you. I wanted to agree with Dr. Schwetz in terms of the importance of looking at the 407 in terms of process in transparency in terms of Subpart D. Another thing I think is important following up on what Dr. Prentice just said and in light of Kennedy Krieger is what is the responsibility of researchers who are not providing services, but become aware of certain information that participants might need or want? And I think that's a very gray area and can create those kinds of legal problems to which there is not necessarily sufficient guidelines. And I will say a third emphasis needs to be on looking at the consistency among Subparts B, C and D. For example, C has a very different definition of minimal risk than B, D is applied to children, so prisoners have a different definition than children do. The extent to which an IRB knows whether or not they should be following Subpart B or D when an infant is born with questionable liability. How we deal with the issue of research involving pregnant adolescents which also may sit under both B and D, and so I think that a consistency issue in kind of looking at those three subparts are going to be important. And I wanted to also support the notion that research is critical, as Dr. Weiner and others have said. And we want to make sure that, through consistency, we have the handling of good research that benefits and protects the participant. CHAIR PRENTICE: Thank you. I'll try to maintain our schedule. Where is Ms. Cooper? Ah, there you are. Okay. Karena has prepared an absolutely fantastic PowerPoint presentation on Subpart C, and I'm sure you're going to regret not being able to see what she has done, but she will have the same challenge as I did to try to describe to you verbally what is normally on slides. And I have to tell you that my training is as of anatomist and if you know anything about anatomists, they are totally dependent upon the visual, because after all that's what an anatomist is all about. So I spent 25 years teaching medical students utilizing visuals, so it's a disadvantage for me. I hope it's not as much of a disadvantage for you, Karena. I think we're ready. MS. COOPER: There's a handout in the back of the slides that I have prepared. It's called "Prisoner Research - Subpart C." Can you all hear? Hello. My name is Karena Cooper and I currently handle most of the Subpart C issues, including the prisoner research certifications at the Office for Human Research Protections. I'm happy to be here today to present a basic overview of 45 CFR 46, Subpart C, the Department of Health and Human Services Prisoner Research Regulations and to reiterate OHRP's request to SACHRP to address NHRPAC's unfinished business related to the application of Subpart C in today's research environment. There is some confusion in the field about the application of Subpart C and, in fact, OHRP struggles with the application, Subpart C, itself. Therefore, OHRP is asking for general and specific advice from SACHRP relating to both unfinished NHRPAC business and on some other issues dealing with prisoner research. I will give some examples at the end of this presentation of questions that OHRP is asking of SACHRP. OHRP plans to use the recommendations provided by SACHRP in the continued development of a more comprehensive prisoner research guidance document. That would have been my first slide. The prisoner regulations are included in Title 45 of the Code of Federal Regulations, part 46, Subpart C, which was adopted by the Department of Health and Human Services in 1978. Subpart C applies to biomedical and behavioral research conducted and supported by DHHS involving prisoners as subjects. According to the 1978 regulations, the default position is that biomedical and behavioral research conducted or supported by DHHS shall not involve prisoners as subjects. However, there is an exception that is found in Subpart C. If a properly constituted IRB, meaning they have a prisoner representative, amongst other things, reviews a study under Subpart C and makes the seven required findings in the 305(a) and the DHHS Secretary, which has been delegated to OHRP, determines that the research involves one of the four permissible categories listed in 306(a)(2), then the research can proceed to use prisoners. The first major determination that an IRB must make when it looks at a study under Subpart C is whether, in fact, the study does involve prisoners as defined by Subpart C. The Subpart C definition of prisoner means any individual involuntarily confined or detained in a penal institution. This is meant to encompass those that are sentenced under criminal or civil statute. It also encompasses individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial or sentencing. The prong of the definition that gives us the most difficulties in the applications of Subpart C is the one that involves the alternatives to incarceration or prosecution. When IRB and OHRP look at this issue, it is necessary to engage in a fairly fact specific analysis. The question is whether the individuals would be involuntarily detained, whether detained in an "other facility," whether they are detained as an alternative to incarceration or prosecution, and then beyond that you need to look at the level of detention or confinement that is inherent in that situation. It can be a very difficult determination to make. OHRP has interpreted a number of situations to not include Subpart C prisoners. For example, OHRP has said that persons on probation or on parole would not be considered prisoners under Subpart C. Also, persons court adjudicated to attend non-residential treatment programs as an alternative to incarceration while living in the community would not be considered prisoners for Subpart C. And also, persons released from prison to a criminal justice or mental health treatment halfway house are presumptively not prisoners. And again, that's a rather fact specific analysis there. So that was the first determination whether prisoners, as defined by Subpart C, are involved. The second determination, which can be very difficult, is whether the research falls and is listed under Subpart C. This, in fact, is the first required IRB finding under 305(a)(1). Now, there are four categories. The first two involve no more than minimal risk or inconvenience. Category (i) or A, if you have an old reprint of the regulations, is a study of possible causes, effects and processes of incarceration and of criminal behavior that is no more than minimal risk or inconvenience, that's Category (i). Category (ii) is the study of prisons as institutional structures or prisoners as incarcerated persons and that one also can be no more than minimal risk or inconvenience. Now, minimal risk is defined in Subpart C differently than it is defined in Subpart A. Minimal risk in Subpart C is the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives or in the routine medical, dental or psychological examination of healthy persons. It is important to remember that the point of reference here is the healthy unincarcerated person. Now, the other two categories, Category (iii) and (iv) or C and D, depending on your reprint, do not specify whether they should be minimal risk or greater than minimal risk. Category (iii) is research on conditions particularly affecting prisoners as a class. In the regulations themselves examples are provided. Vaccine trials and other research on hepatitis, which is much more prevalent in prisons than elsewhere and research on social and psychological problems, such as alcoholism, drug addiction and sexual assaults. It should be noted that this category automatically triggers a secretarial consultation with experts. I'll return to that in a moment. The last category, Category (iv) is research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject. This category may trigger a secretarial consultation with experts if the study involves the assignment of prisoners to control groups which may not benefit from the research. Now, this has been a difficult issue. OHRP's interpretation of the Subpart C control group would be a study arm that includes a placebo, a study arm that includes standard of care, treatment as usual or services as usual. The typical point of reference in making this determination is the specific prison site. So Category (iii) automatically triggers a secretarial consultation with experts. Category (iv) may trigger it under those circumstances I have just mentioned. And the regs say that the study may proceed only after the Secretary has consulted with appropriate experts, including experts in penology, medicine and ethics and published notice in the Federal Register of the intent to approve such research. This process usually takes at least six months from the date that OHRP receives a proper prisoner certification letter and the attached research proposal. In addition to choosing the category under 306, the IRB is required to make six other findings. And, in fact, when the institution or IRB sends a prisoner certification letter to OHRP, the minimum requirement for that letter is that they, in fact, certify that they have met all seven requirements in 305. Subpart C is unique among the subparts in that it has a written certification requirement, and this is the way it works. For DHHS conducted or supported studies, the IRB reviews the study under Subpart C making sure the IRB is properly constituted as is spelled out in 304, which is in Subpart C. And the IRB makes its Subpart C findings. Then the institution or the IRB sends a prisoner research certification letter and attaches the research proposal and sends it to OHRP. The research proposal is basically whatever the IRB reviewed when they were reviewing the study. Upon receipt of this information, OHRP makes a determination regarding the categories, which is spelled out in 306, and then OHRP sends a written determination letter back to the institution or the IRB. So it's, in essence, a loop. The IRB has to review and send the letter. OHRP has to review and send the letter back. This is all prior to the involvement of prisoners in this research. Slide 19 gives a breakdown of the prisoner certifications received in the past four years. There have been over 200 received since the year 2000. I don't know if you can see, it's probably fairly small in the chart, but of the four categories, Category (i) and Category (iv), are the categories most often chosen for the research that OHRP has reviewed. I should mention that recently on June 20, 2003, the Secretary of DHHS approved a waiver for epidemiological studies. In this waiver, the Secretary has waived the applicability of two different provisions under Subpart C. Basically, the provisions are waived that the IRB has to choose one of the four categories I mentioned and that OHRP has to decide whether one of those four categories actually works. Those are the parts that is actually waived, and the Secretary will waive them for epidemiological studies. The waiver only applies to studies in which the sole purpose of the study is to either describe the prevalence or incidence of a disease by identifying all cases or to study the potential risk factor associations for disease. So it's fairly narrow here. The institution must still certify to OHRP that they fulfilled the duties under 305. Now, remember, they don't have to make the first finding, that's what the waiver is about. But they have to make findings 2 through 7. They must certify that their research is no more than minimal risk and no more than inconvenience, and that prisoners are not a particular focus of the study. Now, there are three basic reasons why an IRB would be asked to review a study under Subpart C. If a study is designed to be conducted in a prison setting or using prisoners, that would be one scenario. Actually, that's not the most common scenario, interestingly enough. The second scenario would be if it's a non-prison setting that involves an at risk study population, meaning at risk for incarceration or reincarceration. An example of this would be persons on probation or substance abusers. A very common scenario here is when the investigator is aware that the study population is at-risk for incarceration, but wants to conduct follow-up studies using those persons. So the investigator will ask the IRB to prospectively review the study under Subpart C. The other situation is when a subject is in a non-prisoner study, which was not previously reviewed under Subpart C, and the subject becomes incarcerated. That invokes Subpart C, and then all the regular procedures of Subpart C would need to be followed. So when a subject, becomes a Subpart C prisoner and the study has not been reviewed and certified under Subpart C, the study must be reviewed by the IRB under Subpart C, certified to OHRP, OHRP must determine that it falls into one of the categories. If there is a secretarial consultation that needs to happen, that would happen at that point. The IRB is notified when the PI can actually include those prisoners or continue the involvement of that prisoner in the study. Now, as I mentioned, there is a number of challenges in dealing with Subpart C that IRBs struggle with a number of things as does OHRP. IRBs struggle with finding suitable prisoner representatives to add to the IRB roster. Both IRBs and OHRP struggle with applying the Subpart C definition of prisoner and determining whether the research falls into one of those four categories. It's also challenging to determine what minimal risk means in a prison setting and, in particular, given to issues of confidentiality here, an element of coercion that seems to be inherent in a prison setting. And it is also challenging for the IRBs and the PIs to complete the prisoner certification process prior to the involvement of any prisoners in that research. So OHRP is requesting that SACHRP address some of the unfinished NHRPAC business relating to Subpart C. In general, OHRP would like SACHRP to consider whether or not Subpart C is adequate for what it is intended to do. And if not, provide recommendations for revision. Is this current Subpart C adequate to ensure appropriate inclusion and avoid inappropriate exclusion of prisoners in research? Are the current four categories sufficient or should more categories be added? Should the requirement that institutions certify to the Secretary that the IRB has fulfilled its duties under Subpart C? Should that be retained? Should the requirement that the Secretary judge that the research involves solely one of the four categories of research be retained? And then there are other questions that OHRP is posing to SACHRP. These are just a few of them. Should Subpart C apply to research involving a subject who is not a prisoner, but later becomes one during the study? What should the term prisoner encompass and what is the appropriate background and expertise for an IRB prisoner representative? So Subpart C is available on the OHRP website. Also available on the OHRP website is the May 23, 2003 revision of the OHRP Prisoner Research Guidance document. Thank you for your attention. CHAIR PRENTICE: Thank you, Ms. Cooper. You know when the National Commission formulated their recommendations involving additional protections for prisoners, they considered that to be one of their priorities, and it's not surprising that up until about the early 1970s every Phase one drug trial was conducted in this nation's prisons. Pharmaceutical companies, as a matter of fact, had laboratories in the prisons. So the National Commission was very, very concerned about the vulnerability of prisoners to coercion, so they made this as one of their priorities, and, of course, that resulted in the additional protections for prisoners being issued. However, they are 25 years-old and perhaps they need to be revisited. And one of the things that I find curious is that the regulations require IRBs to basically certify to the Secretary via OHRP that all the requirements of Subpart C have been met. We don't have to do that for any other subject population, but we have to do that for prisoners. So that's one of the things that we're asked to look at is that really necessary? As a matter of fact, it's my understanding that a lot of IRBs are not even aware of this particular requirement in the regulations. So consequently, OHRP may not be getting all of the certifications with regard to research involving prisoners conducted in this country. And the funding agencies are not insuring that such certifications have been submitted to OHRP, that's my understanding. So we need to look at that. One of the things that I'm concerned about is the question of justice. I think that the Subpart C regulations, depending upon how they are interpreted, are quite restrictive, and in some respects investigators are reticent to conduct research involving prisoners, because, in their view, they are so restrictive. There is an awful lot of clinical research that could be conducted in prisons that is not conducted in prisons, simply because investigators don't want to go through the difficulties of trying to get such research approved, first, by the IRB, by OHRP and also by the prisons themselves. So I think it is timely that we relook at this particular section of the regulations. Okay. Any questions? Yes? DR. HARRIS: I'm Nigel Harris. I just needed some clarification with respect to genetic studies as they involve prisoners. It might be classified as minimal risk, but the implications both for prisoners and other populations are quite enormous and I don't know the degree to which that is considered. CHAIR PRENTICE: Karena, do you want to respond or do you want me to respond? MS. COOPER: We actually haven't seen any certifications that involve genetic research on prisoners. I have not seen any. CHAIR PRENTICE: I will tell you that most IRBs view genetic research as being more than minimal risk, depending upon, you know, the nature of it. DR. GYI: As a point of clarification, when we refer to the regulations, Ms. Cooper, that you have cited, they are not FDA regulated products. And so there's a little bit of a disconnect in terms of how we get IRBs and other groups to be in compliance with those regulations and perhaps this is a topic for a subgroup discussion, but it seems to me that FDA regulations don't address prisoner research and I'm looking for some help here, but I don't think that FDA has the same regulations as 45 CFR 46 does. So we need to bridge that gap. CHAIR PRENTICE: No, you're quite correct. As a matter of fact, FDA did propose additional protections for prisoners and a prisoner sued them over depriving the prisoner from his rights to participate in research, and they were withdrawn. I'm sure that David Lepay knows more about that than I do, and they have never been issued. However, if you look at the 21 CFR 56, the basic protections, there is a reference to additional protections for subjects who are vulnerable and prisons would be included in that section. There is just no set requirements as there is under HHS regulations. So one would hope that any IRB reviewing FDA regulated research and, you know, it would not necessarily be subject to the HHS regulations, would apply or at least elements of Subpart C. But you make a good point that there is a disconnect between the two. BOARD MEMBER KORNETSKY: Along those same lines, I think it's important if Karena clarified for institutions that have multiple project assurances, but are reviewing protocols that are not federally funded, whether OHRP, what they require, whether they require that certification, and there was a lot of confusion about that. MS. COOPER: OHRP only requires certification for studies that are conducted or supported by the Department of Health and Human Services. If an institution has an assurance where they have voluntarily agreed to apply 45 CFR 46 to all research regardless of funding, they should follow the standards of Subpart C when they do their review. However, they are not required to certify to OHRP. CHAIR PRENTICE: Karena, could you comment on OHRP's interpretation of the minimal risk-relative to the healthy person standard? Is it the healthy non-incarcerated person? MS. COOPER: Yes, yes, it is. CHAIR PRENTICE: Yes, Dr. Hauser? DR. HAUSER: Ernie, just to drill down a little bit on your use of the word justice, would one example be a prisoner who is diagnosed with an unusual tumor for which there may be only one potential treatment that is investigational, and because that individual is a prisoner, would not be included in the clinical trial and may not have the opportunity for treatment? CHAIR PRENTICE: That's a very good example. Yes. I mean, we have, obviously, a state prison in Nebraska, and I guarantee you the prisoners don't have access to the latest investigational therapies at my institution or any other known institution in the state, and I suspect that that's the same, you know, elsewhere. Also, an issue, of course, of who is going to pay for this. As you know, if you need a peripheral stem cell transplantation, an experimental protocol, you come to my medical center at the University of Minnesota, they're going to ask you well, can you pay for this? And if you can pay for it, then you get it. If you can't pay for it, you sell the farm, you take out a second mortgage or you don't get it. That's kind of the way medicine works in this country. Any other questions? Okay. Thank you, Karena. We're going to take a 15 minute break, and then we're going to reconvene. (Whereupon, at 9:59 a.m. a recess until 10:19 a.m.) CHAIR PRENTICE: Okay, everybody, let's try to get started again. Okay, ladies and gentlemen, let's get going again. If everybody could take their seats, please? Okay. Good, whistle, Christine, you can do that. Okay. I got a microphone. I got PowerPoint. The only thing I don't have is a pointer. So at least we're two-thirds of the way there. Does anybody have a pointer? Jeff, you're amazing. That's Jeff Cohen, formerly the educational director at OHRP, and he has come to the rescue here with his computer loaded with my CD and a pointer now. So thank you for that, Jeff. As I indicated earlier, and so did Dr. Schwetz, one of the reports that NHRPAC worked on was 45 CFR 46, Subpart D, which is additional protections for children. And if we go back to the National Commission's days, that was a subject population that they were very concerned about as a consequence of studies, such as Willowbrook, I'm sure, the hepatitis study that all of you, I'm sure, know about. So those regulations were issued in 1978 or at least the report of the National Commission was issued in 1978, and then the additional protections were issued in '83. So they are about 20 years-old. And NHRPAC was asked to look at those additional protections and provide recommendations and guidance to HHS. So recognizing the fact that perhaps not everybody here is familiar with Subpart D, as perhaps you were not familiar with Subpart C, and that would include some members of the Committee. I have taken the liberty of developing a very brief overview of these regulations and to talk about what some of the issues are. As I indicated a moment ago, the report of the National Commission led to the promulgation of additional protections for children involved in research, and this report was issued in 1978. It took a while for the regulations to actually be issued, but they were issued March 8, 1983. Now, it is interesting to note that FDA did not have similar additional protections for children involved in research until April 17, 2001, when the Children's Health Act of 2000 required FDA to ensure that FDA regulated clinical investigations complied with Subpart D. So FDA came up with the regulations at 21 CFR 50, Subpart D, which is referred to as an interim final rule. Now, for those of us that are not in Government, what in the hell is an interim final rule? As far as I can tell, it's a final rule, but you can modify it without having to go through some kind of incredible review process. Is that roughly correct, David? DR. LEPAY: Yes, I would say so, yes. CHAIR PRENTICE: It's enforceable at this point, but it could be changed. DR. LEPAY: It will be finalized. CHAIR PRENTICE: Will be finalized. Now, these are the categories of pediatric research. In the HHS regulations, we've got 46.404, 46.405, 46.406 and 46.407 and these are the equivalent Subpart D FDA categories. And by the way, with Subpart D, the HHS regulations in Subpart D and the FDA regulations are pretty similar with some exceptions. So I'm only going to be talking about the categories in the HHS regulations, but bear in mind that they also apply to the FDA rule. Now, if you analyze these regulations in terms of their requirements, you will see that they are based upon a risk-benefit protections escalation principle. What does that mean? That basically means that as the risk of the research increases in relation to the absence of direct benefit to the subject, to the child, the criteria for IRB approval under Subpart D becomes more stringent, as it should. As risk increases, no prospect of direct subject benefit to an individual child participating in research, there ought to be additional protections in place, that only makes good ethical sense. And this risk escalations protections principle is based upon a risk-threshold, which is called minimal risk. And you'll understand in a moment how that works. Now, this is the definition of minimal risk in the HHS and FDA regulations. They have the same definition of minimal risk. You can see it means probability and magnitude of harm or discomfort anticipated in the research are not great in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Now, note, there is no qualification of what is meant by daily life. Daily life of whom? Daily life of the research subject or just daily life in general, in the general population. So that's a lack of clarity that's in the regulations, even though the preamble of the regulations, which doesn't have regulatory force, did address what was meant by that. So I indicated earlier that IRBs have been utilizing different interpretations of what minimal risk really means. Some utilizing an absolute standard which says daily life of a healthy child in the general population and others utilizing the daily life of the individual research subject. Now, NHRPAC was asked to look at what minimal risk meant, and NHRPAC, in their report, provided guidance. And you can see that NHRPAC is recommending that daily life be interpreted to mean the daily life of healthy children in the general population. And that the IRB should consider whether the risks are comparable to the risks that parents may ordinarily allow their children to experience in the course of daily life or as a consequence of routine tests, utilizing what is called an equivalency of risk basis. And that's a very, very important recommendation, because I can't tell you how many research protocols I have reviewed where IRBs have interpreted minimal risk utilizing a relative standard and the risks have been very, very significant and clearly inappropriately interpreted. Of interventions by risk classification, on the left side we've got interventions that are no more than minimal risk, things like blood sampling, chest x-ray, urine collection (via bag), an MRI providing there is no sedation, minimal exercise, standard testing, that sort of thing. And over on this side, we've got some greater than minimal risk procedures. This is the first category of research 404, research not involving greater than minimal risk, and the only additional protections are these: Assent of the children and permission of their parents or guardians for them to participate in the research. There is no need for additional protections beyond these, because of the fact that the research is classified as no more than minimal risk. Now, NHRPAC was going to consider the concept of assent and permission and it meant to develop guidance and recommendations for HHS, but this was one of the areas of unfinished business, so SACHRP will take up where NHRPAC left off and look at this issue. The next category is research involving greater than minimal risk, but the research offers the prospect of direct benefit to the individual subjects, to the children participating in the research. There are some requirements. The risk has got to be justified by the anticipated benefit to the subjects, and that's different than the basic protections in Subpart A where the risk simply has to be justified by benefit. There could be benefit only to society and none to the subject. But in category 46.405, there has to be benefit to the individual child participating in the research. And the relation of the anticipated benefit to the risk has got to be at least as favorable as that presented by available alternatives. And this raises the issue of equipoise. Not allowing a child in a clinical trial where there are alternatives that offer a greater prospect of therapeutic benefit. You might be able to do that in research involving adults, but you can't do that in research involving children under 405, so the IRB has got to do this analysis. And once again, assent and permission of parents. Now, NHRPAC decided to consider the requirements of 405 and the meaning of direct subject benefit in a future report. So once again, this would be an issue for SACHRP to look at. And how you define direct benefit is not exactly black and white. I can tell you that our IRB had many debates about whether or not there was sufficient direct subject benefit that justified the risks in a particular research protocol, because it wasn't always clear. This (46.406) is a really problematic category in Subpart D. This is research involving greater than minimal risk, but there is no prospect of direct benefit to any of the children participating. But the research is likely to yield generalizable knowledge about the subject's disorder or condition. So we have a number of terms in here that NHRPAC looked at. Let's look at the requirements. First, in order for research to be approvable under 406, the risk presented to the child participant must not be any more than a minor increase over minimal risk. So you can see how important it is to define minimal risk as your threshold starting point before you can figure out what a minor increase is over this threshold level of risk. The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social or educational situations. So here we see other words that become very important, commensurate, commensurability, what does that mean? Now, the National Commission's report, which was issued in '78, they provided some guidance on what is a minor increase over minimal risk. They said a risk which while it goes beyond the narrow boundaries of minimal risk poses no significant threat to the child's health or well-being. Now, that doesn't really tell you a lot. With all respect to the National Commission's work, to me that doesn't tell me anything. In the HHS and FDA regulations, they don't provide any definition, and they leave it to the judgment of the IRB on a case by case basis. Once again, that doesn't provide any guidance, either. I think that IRBs need guidance on this issue. So NHRPAC, in their work, did provide guidance and they utilized a relative standard for a minor increase over minimal risk and an absolute standard for minimal risk. So basically, this means more additional risk, but only a small amount allowable for sick children than for healthy children would constitute a minor increase over minimal risk, which is based upon the idea that commensurability applies to both experiences and the associated risks, and that the intervention would present an experience and associated risk that is reasonably commensurate with those that the child are familiar with. And NHRPAC provided some examples of what they felt would be minor increases over minimal risk interventions, based upon this relative standard, in consideration of commensurability, so NHRPAC said urine collection via catheter, minor increase over minimal risk, a lumbar puncture, a skin punch biopsy or a bone marrow aspirate with topical pain relief. There are others that could be included in this list, and it will be SACHRP's charge to look at this list, see whether or not we agree with these recommendations and hopefully expand those to provide further guidance to HHS on the interpretation of this very important term. The third requirement under 406 is that the intervention or procedure is likely to yield generalizable knowledge about the subject's disorder or condition which is of vital importance for understanding or amelioration of the subject disorder or condition. So here we see the terms disorder or condition and vital importance. What do those terms mean? NHRPAC interpreted a disorder to mean disorder as a defined medical disorder. For example, diabetes or a host of other illnesses that affect children. A condition, however, does not need to be a medical condition. It could apply to a predisposition to develop a medical condition in the future. And NHRPAC provided some guidance. An example would be an increased risk of developing a disorder. It might be a genetic-based disorder or obesity. Even a demographic or social economic factor such as poverty where a child lives or the environment in terms of pollution levels could be considered a condition that would fit under 406. And then the final requirement, of course, is assent and permission of parents. Now, the last category of research under Subpart D is 407, that's research not otherwise approvable, but presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children. So what are the requirements? Well, first of all, the IRB has to determine that the research does not meet the other Subpart D categories. In other words, it can't be approved under 404 or 405 or 406. And research presents a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting the health or welfare of children. Now, in order for an HHS funded 407 category, pediatric research project, to be conducted, it has to be reviewed at the level of HHS by a panel of experts. And now that the FDA has their own Subpart D, FDA also is required to have a panel of experts for review of protocols under 54. And this review has got to include the IRB's review, their determination, their rationale for referring it for a 407 review and all of the necessary documentation that would accompany that review. And that is sent to OHRP. A panel is then convened by OHRP and recommendations are forwarded to HHS on whether or not, okay, they are recommending approval of the research under 407. There's an opportunity for public review and comment, and a final decision is made by HHS Secretary on whether or not the research should be conducted. Now, remember that Subpart D was issued in 1983. 407 was part of Subpart D. Now, as far as I know and the OHRP staff can correct me, until 2001 I think there was only one 407 review. Melody, is that correct? Irene? Two, two. Now, what does that mean? That means one of two things. Either there were only two protocols conducted in almost 20 years that really qualified for 407, therefore, there was no need for OPRR to convene a review panel or there were many research projects conducted that should have had a 407 review. In 2001, under the auspices of OHRP, 407 reviews began to take place, and I participated in, I think, three of them as chair of the panel and there were probably four more or something like that that I did not participate in, and there was even one joint review, the pediatric smallpox vaccine protocol, which involved both FDA and HHS in terms of the review. One of the charges of SACHRP will be to review and endorse, clarify or modify, if necessary, NHRPAC recommendations on what they did, their excellent work on 404 and 406, to review the requirements of 405 and provide recommendations to kind of fill in the gaps, to review assent and consent of emancipated minors and permission, what does that mean, and provide recommendations, review recruitment and incentives in pediatric research, review placebo controlled trials in pediatric research, that is really problematic, because you conduct a placebo controlled clinical trial under 405. If it's under 405, you have to find prospect of direct subject benefit, sufficient direct subject benefit to all subjects, including those assigned to the placebo, or do you approve it under 406? We need some guidance on that, so that's an important issue. Consider SACHRP as a venue for 407 reviews. That's probably what we're going to talk about mostly today, at least this afternoon, and the reason for that is this report here, the IOM report. The IOM has a report on pediatric research which is due March 2004. They have been working very hard on interpreting Subpart D and coming up with recommendations. So consequently, it's probably not a fruitful exercise for SACHRP to watch its own endeavor to interpret Subpart D until we see the results of the IOM report and then use that as a platform along with the NHRPAC report for our own work. However, we do want to talk about the utilization of this Committee as a parent Committee for 407 reviews. Now, with the exception of the combined FDA, HHS, dryvax, smallpox vaccine protocol review, they have all occurred at face-to-face meetings located in Bethesda. It was not open to the public. And there were not meetings where consensus was reached on anything. The individual consultants provided individual recommendations, which were then formulated into a report. The dryvax vaccine review did not take place as a face-to-face meeting. It took place involving independent reviewers for both FDA and HHS, who submitted their own independent reports. And then, of course, you perhaps know that eventually that protocol was withdrawn from consideration. So OHRP has been looking at the process of 407 reviews in terms of both efficiency and effectiveness and validity. And we're considering whether it would be appropriate to have 407 panel reviews conducted in the future as a SACHRP subcommittee, which would mean that a subcommittee would exist. It would have members of SACHRP as part of the subcommittee. There would be the addition of other members that are not part of SACHRP. There would be the addition of ad hoc members who have the necessary expertise in the particular area of pediatric research under review. And this meeting would be conducted in a public forum. It would be open. It would be announced in the Federal Register. It would follow sort of all the FACA type rules that you have to follow for this kind of a meeting structure. And the committee would be allowed to reach a consensus and recommendations then could be forwarded to HHS. Now, the FDA has been looking at this particular issue and they are thinking about the possibility in the future of maybe having joint reviews of some kind, but that's still on the table. So this is an issue for consideration by SACHRP today. And that is the end of the PowerPoint. Now, we have time for questions. And by the way, I would like to acknowledge the work of Leslie Ball, Dr. Leslie Ball, who is the individual at OHRP who is working on Subpart D, and I don't know, Leslie, are you on the phone? She was going to call in. Irene, she didn't? Wasn't able to? Couldn't get connected? Wasn't able to? MS. GRADY: She tried. CHAIR PRENTICE: Okay. All right. Well, I want to acknowledge her work. She has produced a number of the handouts that you probably have, and I think that they have been very helpful. Okay. I am going to now sit down and return to the microphone over there. Now that 25 years of teaching medical students is a habit that I can't get out of, and you get a microphone in my hand, it's just I get out of hand. Okay. Questions from members of SACHRP? DR. HARRIS: Can you expand a little more on the thinking with respect to this 407 review by a subcommittee of our Committee? We are going to be very, very busy and the question is whether or not this might be something better done by some other group. CHAIR PRENTICE: Dr. Schwetz, feel free to contribute to the regulatory Governmental rational behind this. But as I understand, to have a committee that meets in the public, it has to have some kind of a home, some kind of a parent committee, and it seemed like it might be logical to have such reviews conducted under the auspices of SACHRP. However, I would not suggest that the parent Committee is going to be doing all the work. There would be individuals who have an interest in pediatric research, and as a matter of fact, three individuals here are serving on the IOM Committee. Perhaps they might choose to serve on a 407 review panel and then there would be other members added. Then when we have our meetings, the recommendations of the subcommittee would be brought to the parent committee for acceptance, if you will. Then SACHRP would in turn forward those recommendations on to HHS. Dr. Schwetz, would you kind of fill in the other gaps that perhaps I'm forgetting about, the federal rationale? EX. SECRETARY SCHWETZ: Well, you've done well, but let me just add a couple more points. In order to have a free standing committee that would meet on a regular basis to review and provide advice, it would have to be a federal Advisory Committee approved committee. And within, I would say probably, all the federal agencies, but I know for HHS for sure, there is an effort to reduce the number of advisory committees rather than continue to make them grow. So we're under pressure to find ways to have this done without forming totally new free standing committees that would work independently. So that's why when we need to have a mechanism that's transparent, and would meet on a regular basis or as needed, but more than just once, we want to be able to draw on expertise broadly. The best way is to find a committee that could house this effort by virtue of its expertise, but form subcommittees underneath that committee and allow the review to be done, but the report to come back to the parent committee for presentation and acceptance by the committee and then it goes on to OHRP and the Department. So it's the limitation in the number of advisory committees that puts us in the position. BOARD MEMBER ADAMS: Dr. Schwetz, do you have any idea what the volume of work would be for this group? How many reviews would we be talking about in a year? EX. SECRETARY SCHWETZ: I would ask some of my other OHRP consultants, but we've done two or three of these in the last six months, and those were some that had been waiting in the queue for a short time, so I would not expect there to be more than a handful during a year. But as Dr. Prentice also pointed out, whether or not we're looking at all -- whether or not all of those that should be coming to our attention are coming to our attention, may not be likely. So I would anticipate, if anything, that number will increase as a mechanism becomes established. DR. POLAN: One comment. If the rationale of decreasing the number of committees makes sense, but following Tom's question, if there is a process that's clearly delineated and publicized for doing these 407 reviews, one might think there would be a lot more of them coming forward. So that if this were to occur, it would be really interesting to monitor what the volume is, because one can see an asymptotic increase. EX. SECRETARY SCHWETZ: I think if that happens, we would be in a position of that activity overwhelming the rest of the activity of this Advisory Committee, which wasn't the intent. And if that is, in fact, what happens and we have evidence that it is likely to continue, I would be happy to make the case that we would have an advisory committee that would be free standing, in fact, constituted. BOARD MEMBER KORNETSKY: If I could just ask a question. What happens if and when SACHRP goes away? Because I think, you know, this is really something that is very important to the pediatric community. I think we probably are not seeing a lot of them because it is so time-intensive and people are either misclassifying or just not doing these things, so if we really want to make this transparent, what would happen then? EX. SECRETARY SCHWETZ: Good question. Because that is something in the future that might happen, I don't know what the answer is, but I would assure you that if I have a role in leading OHRP, I would either find another mechanism or make sure that this advisory -- if something happens to this Advisory Committee, then its replacement is ready to go instead of having a lapse in time. So I have no reason to anticipate, at this point, that the Advisory Committee is going to be terminated at some time. So I'm counting on it continuing. DR. FISHER: I would say, I think, in some sense it's two definitions of advisor. For us to act or some of us to act as a 407 committee assumes that the process works, the criteria are clear, is one of our roles -- the other role that we have as an Advisory Board is to actually look at that process. And as Susan was saying, the extent to which some of the submissions are misclassified. Either they should have been rejected under 406, but they come to 407 or they are not sent on. And so I would be somewhat concerned to be the same body that is in some sense carrying forth the 407 as is, and at the same time critiquing the process. CHAIR PRENTICE: Other comments? BOARD MEMBER BARNES: Oh, you have to hold it. Okay. Thank you. I share some of the Committee members sort of apprehension or anxiety that it is possible that this role could, especially if coupled with the role of reviewing protocols involving prisoners, if the Committee were also called upon to do that, could threaten to overwhelm the agenda of the Committee. But at the same time, I think it's important to note that, you know, we're appointed by the Secretary, and if the Secretary tells us to do something or asks us to do something, I mean, it's my opinion that we should do it. So while following the wishes of the Secretary and those appointed by the Secretary, I do think that in doing that it would be a wise idea to have a system of kind of self monitoring to try to understand how much time is consumed, how much effort is consumed, what the trend lines are in regard to the responsibilities and burdens, and that at the same time that we undertake these responsibilities that at the same time we do that, we also have a kind of continuing report or at least kind of self monitoring with the report back to the Committee, to the general Committee, of how much effort it has taken and how much time it has taken. CHAIR PRENTICE: I appreciate your concerns. As a matter of fact, I did raise those and think about them. Obviously, we need to think about this a great deal more, but it seems to me that if we're going to establish subcommittees and we're going to have one dealing with pediatric research, it might be reasonable to suggest that those key members of SACHRP, who are involved in that particular subcommittee, would have that expertise in pediatric research. And the ethics and regulation of pediatric research might be extremely valuable in serving on a 407 review panel, which is charged with interpreting the regulations, applying the regulations and making recommendations as to the approvability of the research. I can tell you that in terms of my experience on 407 review panels, we had a lot of problems in terms of interpreting and applying the regulations. As a matter of fact, the very first time we were convened in Washington, we more or less had a revolution, and we basically did not review the protocols. We spent our time trying to develop some 407 guidance, which you have. It's not an official OHRP document, but that's what we did, because we said, you know, we have no criteria that we can use to review these protocols. So I don't see that this is going to cause the Committee in general an awful lot of additional work. I wouldn't see the parent Committee taking the recommendations of a subcommittee in terms with the approvability for 407 review and dissecting it and going through it with a fine tooth comb, because you would have your core members, who are the experts already, who have already formulated the recommendations. So you're sort of serving as a bit of a vehicle to pass those recommendations on to HHS. I don't know how you feel about that, Celia? DR. FISHER: I think it's very important. I think having a standing Committee that's going to review that so there is a certain amount of consistency is important. What I am concerned about from previous work on other adjudication committees is is that if the subgroup evaluates a proposal in a certain way based on current regulations, and at the same time the subgroup or the committee proper wants to critique just that process, I think we need to consider and have advice on how that is going to work, because by definition, it means that we are in some sense challenging our own conclusion. So I think that is what needs a certain amount of comment and advice before we would pursue it. BOARD MEMBER ADAMS: Just a general question. I mean, I think I would be more comfortable, and I tend to agree with Mark that if this is something that needs to be done, you know, that we should, in fact, step up. However, I am concerned about the amount of staffing that we actually have and about our ability to add additional persons to participate with some of the deliberations here. Presumably, for this to be written, for the 407 determinations to be written up in such a way that they could be published, there would not be an inconsequential amount of staff work that would need to go into that. And will the appropriate resources be made available to the Committee in order to handle that additional charge? EX. SECRETARY SCHWETZ: I would assume there may be slightly more work than it is now, but we're already doing that staff work. We have people who are spending a lot of their time taking care of the panels now and collecting the information, providing everything ahead of time. So I don't think there would be that much of an additional impact on OHRP. And in terms of other supplementary experts to help the Advisory Committee on the subcommittee, we would help recruit those people, but we would also, just as we do now, go to some of you for the names of experts to help us, so that we can do the panel reviews through the mechanism we have been using. CHAIR PRENTICE: In response to your question, Tom, there is a lot more staff support now at OHRP for these panels than there was back when they started in 2001. I mean, in particular, we have got Irene and we have also got Leslie Ball, who is the pediatrician, and she is the one that prepared, as I indicated earlier, a lot of the materials. I would expect that we would get the kind of staff support that would be needed. We would not be involved in setting up these panels. The product of the subcommittees would come to SACHRP, but that would be it. The rest of it would be left up to OHRP's staff to set up the panels, and the only involvement of SACHRP in terms of the actual reviews would be whatever members of SACHRP that are serving on these 407 review panels, and they would be contacted and scheduled and a meeting would be arranged, and then eventually, their product, their review product, would come to the parent Committee for consideration as part of our agenda. One of the problems with previous 407 reviews has been the delay. It has taken months and months, sometimes perhaps even years. That is, obviously, unacceptable. We have got to figure out a way to make the process of 407 review efficient. We have got to find a way to ensure that institutions are not reluctant to submit for a 407 review. You got to remember that it's never going to get to the 407 panel unless an institution, the IRB, reviews a research protocol and says, you know, we can't approve this under 405 or 406. Right now, they are massaging the regulations, at least the ones who know enough about the regulations to carry out that kind of a massage to figure out a way not to refer things for 407, because it takes so long. And there is another aspect. I think that in consideration of the nature of a 407 type of research project, there has to be some kind of an open meeting where the public has an opportunity, you know, to comment, as opposed to the way it has been done, you know, up to now with the exception of the FDA HHS review, which was put on a website. I think the public deserves that. It seems to me that with appropriate staff support, it may be something that SACHRP could handle. And I also want to mention that there are other areas that require expert reviews. Subpart C is one and Subpart B is another. I have been on one Subpart C panel, I think, about eight years ago. I don't know if there has ever been any others, but I can tell you, as I did earlier relative to the pediatric research, there is probably a lot of research out there that probably should go through a Subpart C review panel at the Secretary's level. You know, the idea for us to discuss is also including the Subpart C reviews under the auspices of the SACHRP parent committee, as well as Subpart B. Susan? DR. WEINER: Is there a way to solve this that might solve the organizational issue of having it as a public committee, and balance the burden on the members of this Committee, and also separate the functions of reviewing policy and reviewing protocols by simply having a rotating liaison from this Committee to serve on a 407 panel, since I presume that this Committee would not be approving or re-reviewing the decisions that the panel would make? And that way, at least we would be able, as advisors, to maintain the independence with respect to policy. EX. SECRETARY SCHWETZ: The first question is is there a rule of having a specified number of members of a committee on a subcommittee, and the answer is yes, and it's generally considered to be two, but I know of a lot of subcommittees that are run with one member from the parent committee. So I would be happy to defend one member of the parent committee serving as the chair of the subcommittee, and I think I can defend that depending on the workload and all the rest of the workload that this Committee is likely to have. So I would be very happy if we can get by with one. If there are times when we need a different one, if we want to rotate it, that is permissible, as far as I'm concerned, depending on your willingness to serve as a chair of a subcommittee, but it would be good. Two would meet the requirements. I am willing to justify one and see how that goes. CHAIR PRENTICE: Mark? BOARD MEMBER BARNES: Aside from the possibility of perhaps solving the kind of person power issue with one person from this Committee serving as the chairperson of a protocol review committee for purposes of pediatric research review, aside from that, I think there is an answer to Celia's question about how a committee could both process applications or review them or have one of the representatives do that while, at the same time, critiquing the process. I think, many times that these protocols would come through a review, then they would be either approvable or not approvable under any interpretation of the regulations that might be offered. There is probably a minority of times, but a significant minority of times, which these issues that were defined by NHRPAC and that will be, you know, reviewed and redefined perhaps by this Committee, would, in fact, present policy issues that would not be resolvable at the review level. And, at that point, there actually is a way in which one process could reinforce the other, because if we had a person who was the chair of the review panel from this Committee, and then the review panel, as it did its work, reached an impasse about an issue or reached an issue that was really not clearly defined in the regulations and guidance, then the review panel would simply, I think this is one method of proceeding, make a decision, would be transparent about the conflict or the ambiguity that it sees, comes down on one side of the issue or the other, and then that would be transparent. It would be clear, explicit in the report that would be written up or the minutes that would be written up by the OHRP staff, which in turn would be transmitted to this Committee, and this Committee would really be, at that point, reviewing the interpretation that was decided upon by the review committee. And, actually, in that way, you know, some of these ambiguities might actually be made very explicit and clear for the policy level review of this particular full Committee. DR. FISHER: I think that sounds very attractive. I would also think then that the chair would recuse him or herself from that particular vote. Although, it might represent the opinion of the Committee. CHAIR PRENTICE: I think those are two good points. Mark, your comments remind me that sometimes issues don't really surface until you have to address them, and then you begin to think about them. It may be that by having subcommittees reviewing these protocols, identify and address issues that will assist us in our work here in terms of formulating recommendations on pediatric research. And I agree with you, Celia, about the chair or whoever else recusing themselves. Susan, I would be interested in hearing what you have to say about this. You are at Boston Children's Hospital. Obviously, you have a very deep interest in this whole area, and you were on NHRPAC, and you are part of the IOM effort. So what is your view on what we're discussing? BOARD MEMBER KORNETSKY: Well, you know, I think it makes sense. I understand through the boundaries of federal advisory committees and constituting them. I think there is a strong interest in seeing this process up and running by the IRB community. I think the IRB community has been frustrated, you know, with this and the amount of time. I do have, as I mentioned from my question, concerns about continuity, because I think that would be a disservice to get something up and running and then for that to, you know, go away while we figure out what else. So I think that we need to think about this not only intermediate, but perhaps if we are serving this function, also at the same time to be thinking about, you know, the future as far as if this Committee exists and also as far as the volume issues that Dr. Schwetz brought up. I think there is some benefit in having people from this group involved. For me, at least, I learned best when the real sort of cases are present in front of me. I think we can all talk in the abstract, but when you get those actual issues and cases to struggle with, you can sort of test sometimes the policies and issues that you think you defined condition right or wrong, and then something is right in front of you. So I personally like to learn by that. I think it's also very important, I think one of the frustrations and, I think, once this Committee gets up and going is to really have a mechanism to feed back to the IRB community and the public the decisions even if it's things that are sent for 407s that were determined to not fall within those categories. I think that is probably the best type of learning that IRBs can then take with them and say well, this is not the type of thing that we have to apply for a 407 or this is something questionable. So, you know, I think in general that I am in favor. I obviously have some of the same concerns about it, but I think there probably is something that we can probably work out, and I think it would be of very much importance to the community that we get going on something. CHAIR PRENTICE: Other comments? Felix, from an independent IRB perspective, how do you feel about that? DR. GYI: A lot of the concerns have been raised with respect to what the Committee members might be faced with. The question that I have that perhaps we haven't put on the table so far is, we have talked about pediatric research in light of biomedical studies, and as we know, there is a huge debate on how non-biomedical behavioral sciences are reviewed, and the tensions that exist even on the institutional review boards that are housed with expertise under their umbrella. And I wonder where 407 is going with respect to pediatric behavioral studies and what this Committee's role and charge might be. Clearly, there is a great need for all IRBs to be educated on a determination of acceptability of pediatric studies, and part of my concern is how do we disseminate that information to all IRBs, independent or otherwise, and superimposing on that is the role of behavioral studies, although we haven't specifically spoken about that. CHAIR PRENTICE: That's a good point. As we all know, there is only one set of regulations. They are not dissected out for behavioral social science research versus biomedical research, and some of the criticism of social sciences is that the regulations were not written for behavioral social science research, and they are being applied in a biomedical sort of framework, and we recognize that. I don't see very many studies that are in the behavioral social science arena, you know, really requiring a 407 review. There could be some, but I don't think it would be very often that that would happen, but I do agree with you that they need to be educated about that, because when an IRB reviews any research project involving children, they have to apply Subpart D. It doesn't matter what the nature of the research is unless it's exempt. Nancy, were you going to say something? Oh. DR. HAUSER: I don't know exactly where this comment falls, but we frequently see situations where mature adolescents, who are essentially adults, have conditions which would be treated potentially well with investigative devices. But because they are over 18, they are not considered for the protocol, because the protocol specifies that you must be under 18 in order to qualify. My question is, my comment, is this a scenario that we will get into or is this something we're going to talk about this afternoon or perhaps not talk about at all? The second question I have is in our deliberations regarding these recommendations, will we talk about permission by mature adolescents without parental consent? CHAIR PRENTICE: The answer to your first question is that we probably won't talk about these issues in any kind of detail this afternoon. However, in terms of NHRPAC's unfinished business, the areas of assent and parental permission, which would include all of the issues that you raised is something that we need to address. The emancipated minor and what they can consent to and what they cannot consent to is a problem. It has been a problem for my IRB for many, many years, and we would certainly welcome further guidance in terms of how we go about enrolling minors into research protocols and balancing their rights along with the rights of parents to, you know, consent on behalf of their children and sort of protect them. That's the role of a parent. So it's not an easy issue to resolve, but it's certainly something that we want to take a look at. Mary, you have been a little bit quiet. DR. POLAN: Well, as I have sat and listened to the discussion, something completely -- two things that occurred to me. One is the desirability of having some generalizable processes for bringing into conjunction regulations with the FDA, with NIH, with HHS, so that there is some consistency across the board. And then as Felix said, communicating this back to IRBs, our IRBs work very hard and they are composed of individual faculty members who have completely total jobs. I mean, this is gratis work and it takes a lot of time. So how do we communicate this to IRBs and further, to individual investigators, because if you want to make a system that works well, really the investigators have to understand what the process is, so that they don't get into a situation where they get things bounced back from an IRB, which has then had it bounced back, because it doesn't fit regulations. So what has occurred to me is should we be looking at communication issues, how we're going to talk to IRBs, so that you make the system work better, because issues of six month turnarounds or year long turnarounds really don't facilitate research for anybody in any circumstance. And I don't know if that is part of this Committee's charge, but it seems to me that we could work in a vacuum and affect precious little unless we communicate it. CHAIR PRENTICE: I think we might be addressing some of the issues that you just -- this afternoon when we talk about the relationship between OHRP and FDA and independent human research protection program accrediting bodies, such as AAHRPP and NCQA-JCAHO. In order for an institution to become, and I can only speak on behalf of AAHRPP, because I am not familiar with NCQA-JCAHO as much, but I am on the AAHRPP council, and I have been on an AAHRPP site visit. I know that when we go out and review an institution's HRPP, we look at not only compliance with all applicable federal regulations, but we also look at the overall operation of the IRB and the efficiency of the IRB. We interview investigators and we try to find out what their perspective is in terms of their interactions with the IRB. And if we were to find that there is absolutely, you know, unnecessary delay in terms of submission of a protocol to ultimate review and approval, that would indicate inefficiencies in the system, which perhaps is due to lack of resources, which would be commented upon. So perhaps accreditation will help resolve some of those problems. Another contributing factor to delays is the fear of litigation, the practice of IRB defensivism where you dot every I, you cross every T, you check everything, you make sure your records are complete, which takes a lot of time. And if you have inadequate resources or perhaps untrained staff, that tends to delay the review process. So these are all problems that need to ultimately be addressed, but I'm not so sure that, you know, this is the venue where we're going to be the ones that correct these deficiencies in the IRB system. DR. HARRIS: At the risk of repeating what you said, and I really did want to speak some more to that this afternoon, about the role of non-federal accrediting bodies, because I believe, you know, this is really the best opportunity to alter a whole community culture. There is nothing like accreditation to grab the attention of institutional leaders, as well as a whole community, and I believe that we talk a lot about IRBs, but IRBs really, unless they are part of a community that feel the same way and, in fact, have accrediting standards to which they, you know, have to live by, I think you are never going to get to wherever you want to be. So I want to again say that I believe this is going to be an important agenda subject this afternoon and a priority I would like to speak to later. CHAIR PRENTICE: Yes. I would like to endorse what you say. I have been involved in both the ethics and regulation of human research, as well as animal research. We have an accrediting body for animal care and use programs that is called AAALAC International. It has been around since the 1960s, and most premier research institutions are AAALAC accredited. I think the count is somewhere around 650, 700 institutions. And throughout the '80s and the '90s, I often wondered why is it that we think it's important to accredit animal care and use programs, but we don't think it's important to have an accreditation process for human subject protection programs. And I know that there was talk in the '80s and '90s about accreditation, but nothing ever happened. And it would not have happened now, I don't think, if it weren't for the OPRR shutdowns and the OHRP shutdowns of the major research institutions, the shutdown of the West LA VA Medical Center in March of '99, which then precipitated an uproar in Congress, which led to the issuance of an RFP, and there were bids to get the contract to develop an accreditation system for the VA system, which in turn led to another organization coming on board called AAHRPP. And now, we have two organizations that are involved, just beginning I might add, in the accreditation of human research protection programs. You note that the term is HRPP now. It's not just IRB. It's HRPP, because a human research protection program encompasses so much more than simply the IRB. It's where the IRB fits in the institution's structure and culture. It's the program for education of investigators, the program for education of IRB members, so forth and so on. I think that accreditation is probably the best thing that has happened to this field, and I would really like to see it pushed from a variety of different levels. I would like to see institutions begin to develop their self studies to apply for accreditation, and I think that's very, very important. It's going to do wonders for the system. It's amazing how institutions pay attention to accrediting bodies. I know from my own experience when we have an AAALAC accreditation site visit, they come in every three years, and they always have a different focus. The last time they came in, the focus was on occupational health, to protect laboratory personnel. And I had to go to the chancellor and say listen, we have an inadequate occupational health program here. He said how much is it going to cost? And I said oh, maybe $200,000, and the money is right there. On the other hand, I have to tell you that I went to the chancellor two or three years ago and said, you know, I really need more staff for my IRB, he would say, you know, everybody needs more staff. Accreditation will force administrations into providing the resources needed to ensure that we have adequate systems in place. So it's an important agenda item, Nigel, and so we're going to talk about that this afternoon, and we'll have representatives from AAHRPP and NCQA on board this afternoon. DR. WEINER: There is an interaction between the two topics we have just been talking about, namely pediatrics, the research on kids and the question of accreditation. If there is variability from institutions, pediatric institutions, based on IRBs' decisions about research, which we know for a fact there is, which has really a negative impact on kids' access to new therapies. All the trials in pediatric cancer, of course, are multi-institutional trials, almost all the trials are multi-institutional trials, and the standards are inconsistent from institution to institution. What is accreditable with respect to one pediatric institution may not be or at least is questionable with respect to another. So I think that, you know, one of the things that concerns us in the pediatric cancer community has to do with the efficiency of multi and the needs for multi-institutional IRBs. DR. FISHER: When we do take up this subject, I think another thing we need to discuss in terms of your principles of justice, Ernie, is the extent to which we don't place a burden upon smaller institutions that they will not be able to fulfill on an economic level and, therefore, will either cease to participate or cease to conduct the research. And so given we want to, you know, clearly support research, I think the economics of scale will be an important issue to discuss. CHAIR PRENTICE: You make a good point. In part, I think, what you mentioned is responsible for the development of community-based IRBs when one small community hospital really can't support an IRB in an adequate way. They can't do an adequate job, so you have community-based IRBs. Of course, we have independent IRBs that are performing review functions and services. So, you know, I agree with you. And there are small institution IRBs that probably can't become accredited, because they simply don't have the resources. And under those circumstances, perhaps they should use an alternate review mechanism. DR. WEINER: I think pediatrics in particular is a nightmare, because in the Children's Oncology Group, there are 238 separate institutions, and some who can enroll kids in clinical trials, some of whom are quite small. So to be able to take advantage of a more centralized mechanism with the expertise available from larger institutions and relieve local ones of the burden would be tremendous. CHAIR PRENTICE: Well, central IRBs is a possible topic for discussion. As you already know, I'm sure that the NCI has a central IRB body that is already up and running, and there are institutions who are participating in that review. CALGB is one of the co-op groups that we use a central IRB review for. There is talk about expanding that to other co-op groups. One has to wonder how efficient it is for 225 separate IRBs to review one co-op protocol that has already been developed and reviewed scientifically at the NCI level, and then it comes down the pipe to all of these other IRBs, and they really can't alter the protocol. So what they do is they muck around with the consent document, and sometimes they make it worse and sometimes they make it better. But it seems to me that it might not be that cost effective for all of these IRBs to review all the same protocol. So that is another possible topic for us to discuss. Yes, Mary? DR. POLAN: This really doesn't pertain necessarily to the pediatric issues, but something that also I would like to think about whether it is within our purview as a Committee to look at, which is relationships in research, the projects that are done internationally both in developed countries, and particularly in the developing world. Having had some experience with that, it is really difficult when you're dealing with populations of people who are illiterate or who have 14 different tribal languages. I don't know how we or if we should be talking about that, but it would be nice to have some kind of general understanding of how we might deal with other countries and their infrastructures. CHAIR PRENTICE: I'm sure, as you know, within the charter there is a reference to international studies. EX. SECRETARY SCHWETZ: I'm going to say a word first, and the first word is if we can have these lights turned up. The panel is right there by the door. It would be nice if we could have the lights turned up up front here. Well, it's a pleasure for me to be able to introduce two of our colleagues. First of all, Vice Admiral Richard Carmona, Surgeon General and Acting Assistant Secretary for Health. Welcome, Dr. Carmona. And it is certainly an honor for me to be able to introduce Secretary Thompson, Secretary of Health and Human Services. I would just comment also that prior to coming to HHS, he was the Governor of my home state of Wisconsin for 14 years, and we welcome you very much to this meeting. Thank you. SECRETARY THOMPSON: Thank you very much. You got to hold it down? Can you hear me now? Okay. Thank you very much. I am delighted to be introduced by Dr. Bernard Schwetz. He is a wonderful guy and just done an outstanding job ever since I have been here. I found out when he was the Acting Assistant Secretary of FDA that he came from Wisconsin. We have had a bonding relationship, and he has just done a wonderful job, and he is always able to come forth and give it his all and he is doing that again today, and I thank you very much, Bern. It's good to see you again. And the new chairman, Ernest Prentice, thank you so very much. Put that up, so I can see it. And Dr. -- CHAIR PRENTICE: Not yet confirmed. SECRETARY THOMPSON: Well, you're going to be by acclamation, I'm sure. I got a sneaking feeling you're going to be the Chairman. And Surgeon General Carmona and I were in a meeting yesterday with the health insurance presidents and chairman of the companies that insure about 125 million Americans, and we were talking about how we can get America and Americans to change their lifestyle as it relates to eating and nutrition. And we are too fat in America, as we all know, and we're chunky and I have put the whole Department on a diet, including myself, and I have lost 15 pounds and I feel much better about it, and I'm trying to get the whole Department to slim down. If we're going to go out and talk about prevention, we have to look the part, and so Carmona and I are on a crusade to change the lifestyles in America, and we're trying to get America healthier. And that is why all of you are here, because without your support and what you are going to be doing here over the course of the next year, we couldn't be doing the kind of research that is necessary to come up with the kinds of cures and therapies that not only Americans want, but the whole world does. And I just got done meeting with the Minister of Health from Korea who is here with her entourage, and she is here to see how we do things in America, so that she can go back and, hopefully, copy some of the things that we're doing in America. And we have 275 Korean scientists from South Korea that are working at NIH, and we have got several more that are working at CDC, and they are going back and help convince and educate and to integrate some of the stuff and practices that they are learning here back in their country. So it was a very interesting thing, and then to have the opportunity to come up here and first say thank you to each and every one of you for the great jobs that you are doing, the willingness to serve is always a wonderful thing. Going back to when I was Governor, I was always amazed at how many wonderful citizens would stand up and want to serve on committees and assignments with very little fanfare and very little payment, and just willing to serve and do what is necessary to improve Wisconsin. And that has even been excelled by coming out here to Washington and seeing people like you, who are so busy with your daily lives and got so many responsibilities, but are still willing to come and serve the better good of mankind in this country. And I want to personally and publicly thank you. So welcome to the Inaugural Meeting of the Secretary's Advisory Committee on Human Research Protections. I am just delighted that all of you are here. We have reconstituted this Advisory Committee, and given it more responsibilities and started out, and this is the 1st meeting. It's a new mandate and new opportunities, but also new responsibilities. Almost every American benefits from clinical research, as we all know. And the wonderful thing about being Secretary of this great Department, I am amazed at the tremendous caliber and wonderful doctors and researchers and scientists that we have in this great Department. I am absolutely blessed. I think I have the best doctors and researchers and scientists in the world working for this Department, and NIH and CDC and FDA and CMS, and I'm just always overwhelmed by their capabilities. And up at NIH, we were so close, so many breakthroughs. It's absolutely exciting in so many areas. There are so many people out there with hope and optimism waiting for those discoveries. And, of course, we need research subjects in order to accomplish that, and that is where you come in. We stay healthy, because research tells us how to develop those healthy habits and avoid risky behavior. When we do get sick, the medical care available in America is stunningly advanced thanks to innovation, the creativity and, again, clinical research. Clinical research has achieved these great advances thanks to brilliant researchers, which I have already mentioned, foresighted investors, patience, tax payers, fastidious doctors and ordinary people who participate in studies as research subjects. A typical healthy American owes part of his good health to his behavior, part of it to his insurance and his doctor, and part of it to research subjects he or she will never meet. But we are all grateful to these individuals, wonderful individuals who volunteer to participate in research studies and, therefore, because they are willing to participate, you and I have a very special duty to protect them from any harm. And we're here today to entrust that duty to some very honorable Americans. We believe in protecting human beings from harm, because we believe in the dignity of human nature. We want research to help people who need help, and we want to make sure it never hurts those individuals who cooperate in that research. TELECON OPERATOR: This conference is showing no activity. If you would like to continue the conference, press star 1 now. SECRETARY THOMPSON: No activity? Thanks a hell of a lot. Some disinterested Congressman. This Department issued regulations to protect human research subjects. We grounded these regulations on ethical principles, a respect for persons, their beneficence and their justice. HHS has additional protections for various special populations, including prisoners, children, pregnant women and the unborn. Our Office for Human Research Protections has the important and the challenging responsibility of implementing the HHS regulations for the protection of human subjects. And in order to provide the best protection, we look forward to receiving expert outside advice. So I am absolutely delighted today to be able to welcome each of you, the members of our new Advisory Committee on Human Research Protections. I want to welcome you as members to HHS and tell you that we selected you, because we have great confidence in your experience, your dedication and your compassion. I look forward to receiving your advice, and even more importantly, your recommendations. I certainly want to thank my friend Bernard Schwetz and Ernest Prentice for their leadership, Bern Schwetz, who is the acting director of the Office for Human Research Protections, and Ernest Prentice, who is going to be the Chairman of the Advisory Committee. I also want to thank a very special friend of mine in his days of leading the State Medical Society of Wisconsin when I was Governor, Tom Adams, and I thank you very much for being here, as well. Even though you don't live in Wisconsin anymore, you still are very near and dear to me. So, at this time, would all of you, please, stand for the oath of your office and, please, raise your right hand and repeat after me. (Whereupon, the Committee members were sworn in.) SECRETARY THOMPSON: Thank you. Please, be seated. Thank you for your service to the United States Government people. I look forward to learning the outcome of your deliberations today and receiving your report and recommendations in the future. And so, Ernest, I turn it over to you and to Bern and Dr. Carmona to carry on and I wish you well, and thank you again and have a great day. (Applause) CHAIR PRENTICE: All right. Speaking on behalf of the Committee, I really appreciate the fact that Secretary Thompson took the time out of his busy schedule to come to talk to us, and to give us our charge. I think it's indicative of his interest in our future work, and the fact that he is going to take our recommendations seriously. So I am very enthusiastic about the fact that he is involved in our endeavor. I would like to provide anybody here with an opportunity to ask questions or make comments, and if there are none, then we will adjourn for lunch about five minutes early and reconvene at 1:15. Any questions or comments? Where is lunch? I thought you were going to say where is lunch and what is lunch? You know, I was going to make the comment in front of the Secretary, but, unfortunately, he left. I was going to ask him whether or not we were allowed to eat the kind of dinner we ate last night, okay, at the restaurant in Washington. I don't think that it helped anybody's diet last night. Okay. Any comments or questions? Okay. Thank you, everybody, for attending this morning. We will reconvene in an hour and 15 minutes. (Whereupon, the meeting was recessed at 11:52 a.m. to reconvene at 1:29 p.m. this same day.) A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 1:29 p.m. CHAIR PRENTICE: Welcome back, everybody. The agenda for this afternoon's session will be devoted to a SACHRP discussion of priority setting, which will obviously consider many of the topics that we talked about this morning. There will be a period of one hour for public comment for anybody who wishes to address the Committee. So far, we have no formal requests. We'll take a short break. We'll continue our discussion of priority setting, and then we'll have a wrap up, and we need to conclude by 4:30. On the agenda, there is a list of topics, specifically there are seven items. You should all have a copy of that agenda. The first item deals with creating subcommittees of SACHRP to review research protocols that require referral to a panel of experts at the HHS level under Subparts B, C and D. Now, we talked rather extensively this morning about Subpart D and Subpart C. In terms of preliminary work and consideration, OHRP has devoted more time to the issue of whether or not to utilize SACHRP as the parent Committee for 407 panel reviews. So I would like to begin with that particular topic. I would like to reiterate the way this kind of a structure of review might work. When an institution, institutional review board that is, reviews a research protocol involving children and they find that they cannot approve it under 404, 405 or 406 and it is HHS funded, then they should send it for review at the HHS level under the Section 407 of the regulations. Then OHRP in previous times convened a panel to perform those reviews, but it was not an open meeting. We are proposing that a subcommittee of SACHRP, a 407 panel review subcommittee specifically of SACHRP, be appointed to be responsible for reviewing 407 applications. We are proposing that this subcommittee have at least one, preferably two, members from the parent Committee serving on that committee with one of those members as chair perhaps, and that other individuals be appointed to that committee as core members, and then ad hoc members would be appointed, individuals who have the necessary expertise relative to the protocol under review, and that this subcommittee would perform a review. The results of that review would then be given to SACHRP for consideration by the parent Committee. But we are not suggesting that SACHRP would spend a great deal of time re-reviewing the entire protocol and dissecting it and asking for clarification after clarification. If we were to do that, the system simply would not work. So that is the proposal that is on the table. It would be nice if we could come to some agreement on this particular item. If we can't, then we will have to defer it for further discussion at another time. Mark and then Tom. BOARD MEMBER BARNES: In line with our conversation this morning, let me make this as a motion, so that it can be perhaps thought about in that way. Is that all right with you as Chair? CHAIR PRENTICE: Yes. BOARD MEMBER BARNES: Okay. The motion would be this, and that would be that in regard to the pediatric research reviews that must be done by the Department, that we have a subcommittee of SACHRP, which would consist, let's say for purposes of the motion, of two people, two members of this Committee who would be co-chairs of a subcommittee to review that research. The membership of the committee, other than the two co-chairs, will be composed of those people who would be drawn from those with expertise, not necessarily from this Committee, but from whatever selection process might be specified by both the Department and by the SACHRP Committee in general to review and pass on these applications with a report back to the full SACHRP Committee with the presumption being that the full SACHRP Committee would simply approve or respect the judgment of the subcommittee. And when the full SACHRP Committee considered the reports from the subcommittee, then in line of what Celia had said, the two co-chairs would, presumably, recuse themselves from the vote on that if a vote, in fact, were necessary. So that is the motion that I would make. CHAIR PRENTICE: Is there a second? There is a second. There is a motion on the table. It has been seconded. Further discussion, Tom? BOARD MEMBER ADAMS: Point of order and then discussion if I might. Is it your intention before the motion was made, is it your intention to run the Committee basically based on Robert's Rules with a more formal parliamentary type of activity or were you headed more towards running sort of a consensus type of operation here? I just needed some feel from the Chair as to how you want to proceed, whether you're looking for motions and whether you are looking for amendments to motions and that type of thing? CHAIR PRENTICE: I think I would prefer to have motions and seconds, and discussion of those motions and votes utilizing the simple majority for approval of the motion. If that is acceptable to everyone unless you have a different suggestion for our procedure. Susan? BOARD MEMBER KORNETSKY: I just wanted to make a remark about what Mark has proposed, and I think I spoke this morning about generally how I felt about that. I guess my concern is sort of the balance. I mean, if this is really the Committee that is going to be the expert group and we have two chairs, and we have talked a lot about this, when it comes back to the full Committee that the purpose would not be to totally, you know, dissect it. I guess I'm just trying to balance and be a little bit concerned that this Committee as a whole, if we are looked at as the expert group, is just not the rubber stamp of it. I realize the importance of the expertise. And, although, we have people here in pediatrics having read and followed some of the 407s, which I have not been involved with at all, to this point, they are complicated and absolutely, we need external people. But, I guess, I'm just trying to come to some type of comfort level, and I don't know whether that means -- I mean, I know that we all are going to have a lot of work to do. I don't know whether that means perhaps making sure that it's more than two people or one person was making me feel uncomfortable, that one person would be acting on behalf of this Committee's Advisory Group. So I don't know how other -- I mean, I know a lot about 407s. You know, I feel comfortable, but everyone else around this table has to realize that it's really -- they are acting on that, as well, and I just want to make sure whether there is an education issue here that, you know, we maybe need to better educate or let other members know, but I just want to have everyone feel comfortable with that. CHAIR PRENTICE: That's a very good point, and I understand the issue of a comfort level. And I don't like the idea of being put into a position to rubber stamp anything. That's not the way I do things. At the same time, however, we can't have another second review, because that would be terribly inefficient, and we might as well not adopt this kind of a committee review mechanism if it comes to that. So this is a difficult issue that we need to think about. Tom? BOARD MEMBER ADAMS: Susan's point is also the one, which I wanted to address, and that is just simply from the standpoint of the oath that we took as members