DR. SHAPIRO: Thank you very much. We are now going to move into our public comment section and we have a series of people who have signed up which will use up all the time we have allocated. Before public comments, I want to remind all those who give public comments that there is a limit of 5 minutes and out of courtesy of those who come after you, please stick to your 5 minutes. I will let you know when your time is almost up. There have been various requests of people who seem to want to appear in various orders. I'm just going to take this in the order in which they registered. First come, first serve is the only kind of fair way to deal with this, so I'll just ask for a couple of comments from those in the order in which their request arrived with our staff at our office. The first person to speak will be Harold Pinkus, Deputy Medical Director of the American Psychiatric Association. Dr. Pinkus?
DR. PINKUS: The American Psychiatric Association, on behalf of more than 40,000 psychiatric physicians nationally, appreciates the opportunity to comment on the NBAC draft. The guiding principle in our comments is that the interest of participants in research projects comes first. We appreciate the careful and thoughtful deliberation with which the Commission considered these issues as evidenced throughout the report. We agree with the Commission that more attention must be paid with regard to research conducted with persons of potentially impaired capacity and we support many of the recommendations of the Commission. However, we would like to focus our concerns and our comments today on three areas which we believe should be modified. As recommendations are currently drafted, important research will be precluded without providing significant additional protections, an outcome we don't think is intended by the Commission. With some additional modifications, these recommendations could prove beneficial. Our previous conversations with staff have been very productive and we hope to continue them so we can continue with the shared goals that we think we have with the Commission: to provide protections and assure added increments to our knowledge about mental disorders. Many of the concerns we raise today are shared not only by other researchers, but also shared by consumer groups as well. To mention one example, 30 national mental health groups, including several of the leading consumer and family groups, wrote the Commission last Thursday. These groups, including the APA, stated our support for many of the Commission's recommendations, but urged that the report not focus on individuals with mental illness, but instead focus on individuals with impaired decisionmaking. We also particularly call your attention to the October 8th comments of the National Depressive and Manic Depressive Association, as well as NAMI's testimony supporting a more graduated approach to research risk, instead of a two-tiered approach. Our specific concerns are as follows: 1) requiring capacity assessments for every research participant be performed by an independent expert is highly impractical and will not provide meaningful protections for participants with mental illness. Individuals with mild depression or anxiety or sexual dysfunction, primary insomnia, adjustment disorders—all conditions like that are diagnosable mental disorders—are not likely to have a higher incidence of impaired decisionmaking than the general population of potential research participants. Particularly in these cases, the highly burdensome requirement of an independent capacity assessment simply does not make sense and could compromise valuable research. Also, many individuals, even with severe mental disorders such as stabilized bipolar disorder who are functioning quite well will find this requirement intrusive and offensive. Similarly, it appears from your recommendations that independent competency assessment would also be presumed even in minimal risk research, such as questionnaire or observational studies. This would seriously divert resources in situations in which subjects are essentially at no risk from participation. We also recommend that the Commission review the APA policy statement entitled "Guidelines for Assessing the Decision Making Capacity of Potential Research Subjects with Cognitive Impairments." 2) We believe NBAC support for a two-tiered level of risk in the regulatory framework i.e., minimal risk and greater the minimal risk, should be modified. Limiting the calculation of risk in research to these two categories would seriously harm the abilities of scientists to conduct research, particularly research presenting a very low level of risk that potentially may yield important breakthroughs in our ability to treat mental illness. Others have identified important areas of research that would be compromised in this area. We urge NBAC to adopt a more graduated level of risk rather than a simple two-tiered approach. Third, we also believe, and probably most importantly, that your approaching the report, focusing exclusively on individual with mental illness, unnecessarily stigmatizes these individuals and is not based on our current scientific understanding of these illnesses. We are troubled that this focus appears conceptually flawed and logically inconsistent. While the report alludes to the definition of mental illness in DSM-IV, it is unclear to readers whether the Commission intended for conditions that affect central nervous system functioning, but are not commonly considered as mental illnesses, to be included. If the Commission intended their inclusion, then the mental disorders label is not only stigmatizing, but confusing, and does little to help investigators identify those at risk given as noted above, the vast majority of individuals with mental disorders have mild, less-impairing conditions. A more accurate term would be disorders that affect decisionmaking or disorders that affect the functioning of the central nervous system. If the Commission did not intend for these disorders to be included, then their logic for failing to do so is not clear. Why should an individual with a stroke or diminished cognitive function from congestive heart failure be afforded less protection than somebody with Alzheimer's disease or schizophrenia? What is the essential difference? If you are recommending special accommodations for individuals who can't climb a flight of stairs, you wouldn't have a focus on individuals with cardiovascular conditions, thus including people with hypertension and no impairment and excluding people with impairing pulmonary or neurological or other conditions. The costs of these categorizations are high. Not only is there serious stigmatization of a class of individuals on the basis of their condition, but there are important practical implications that undermine the Commission's overall goals. What the report—inadvertently diverting attention from assessing capacity to evaluating mental illness. There is also the point that future progress and understanding in treating mental disorders requires both financial and intellectual resources. The diversion of resources for unnecessary added protections in low-risk situations was discussed earlier. A more serious and subtle diversion is likely to result from the greater perceived barriers in mental illness research, diverting talented young people into other lines of research or out of research altogether. There are already significant barriers, intellectual barriers, many of which are identified by the Commission's report. While these, maybe in some cases, are stimulating intellectual changes, consider the plight of a talented young medical student interested in research, looking ahead to a career path requiring extensive research training and foregoing a more lucrative clinical practice. Additional stigma and barriers unique to mental disorders research as a class are likely to diminish the relative attractiveness of the field, reducing the already limited flow of talent to a very leaky pipeline of research career development in mental illness. We urge the Commission to modify its title, report and recommendations to focus on conditions that may affect decisionmaking capacity and to not apply blanket requirements to individuals with mental disorders. We share with the Commission your goals or providing additional needed projections to individuals with impaired decisionmaking, and look forward to working further with the Commission.
DR. SHAPIRO: Thank you very much. We very much appreciate your coming today. Larry?
DR. MIIKE: Let me ask you, does the existence of the American Psychiatric Association stigmatize people with psychiatric illnesses?
DR. PINKUS: We don't believe so. But I think there's a fundamental difference here.
DR. MIIKE: You've answered my question, thank you.
PROF. CHARO: Oh, Larry. May I ask that he continue with his response, for me?
DR. PINKUS: There's a fundamental difference here. Here you're essentially significantly, in my view, illogically singling out a particular class of individuals on the basis of a particular impairment that is shared by other classes of individuals. And that's, I think, an important problem.
DR. SHAPIRO: Thank you very much. Next to speak is Dr. Leslie Alcorn, Consumer Council President, present member of Board of National Alliance for the Mentally Ill. Mr. Alcorn, thank you for coming here today.
MR. ALCORN: Thank you. Did you say Doctor? I'm afraid not. I want to thank the committee, Mr. Chairman, for this opportunity. First, a couple of clarifications. I am not coming to you as someone who is anti-research or anti-medication or anti-psychiatry. In fact, I support many of those things and take medication myself that has lifesaving qualities for me. So I need to clarify that. Also, I'm not here to have some narrow political posturing or organizational infighting. But I can't argue that the dynamic does exist, but please accept my remarks in the context of the bigger picture. I don't believe in this august body—and I mean that truly—I don't believe I can inform or reveal any great truths. After reviewing earlier testimony, it's clear that the issues have been spelled out. I wouldn't consider it. ... or the well of philosophical and ethical traditions that have produced the ancient verities. Nor am I persuaded that you're in possession of all those facts as it relates to the field of bioethics. Perhaps it's lost in the minutiae of syntax and deliberations, but I want to remind everyone exactly why we have commissions, why we have standards, why we have oversight. Why we have bodies designed to do that, entities. It's because there's evil in the world and that's a fact. There's rapacity, there's single-minded self-interest, duplicity, co-option, human frailty and, all too often, massacre of the innocents that comes from that. That's why you're here. You're here to protect the defenseless. You're a line of defense against all that I've previously invoked. That's why I come before you today. I'm a relatively recent student of bioethics, but I will tell you the research that I've done, no pun intended, I found it absolutely horrifying. So totally antithetical to my career as an advocate, where I've worked to get people on medicine, to get the right medicines, the right amounts. To give them the quality and to return their humanity. And then I discover a particular branch of experiments called psychosis-inducing experiments with challenge studies, drug washouts. How about a little ketamine with your coffee in the morning? Carbon dioxide with your bagel? You can cloak this in all the lab coats and academia and sterile scientific language you want, but this is evil. These kinds of experiments are evil, and they are experiments. There was evil 50 years ago, it will be evil tomorrow and it will be evil 1,000 years from now. And if I know that, then you folks must know it too. And please don't forget why you're here. A doctor who remains unnamed claimed 50 percent of folks with schizophrenia lack insight. But these psychosis-inducing experiments, there seems to be no problem with that batting average—it's very, very high. So the interpretation of what's informed consent and what is not is very alarming. I want to conclude by saying I think it's fairly obvious to me that we are here trying to facilitate research. And in the process of enthroning that, we are attempting to provide some minimal standards of decency for the human beings that are involved in it. And I would submit that that's exactly the opposite of what it should be. We should be attempting to define and defend the sanctity of the individual and then put the research around that. But we seem to have got things backwards here. I don't believe it's possible to maximize the research capability on consenting disabled human beings and protect the sanctity and inviolability of the individual. You either must err on the side of one or on the side of the other. And this has every appearance on erring on the side of science. There's nothing sacrosanct about research. There's everything sacrosanct about the individual, the human life. Let's spell it out—there's billions and billions of dollars tied up in this business. Pharmaceutical money, university grants, research and that is driving, pushing, riding this entire process. That's what is not being discussed here, that's what is kind of unmentioned or between the lines.
DR. SHAPIRO:I don't mean to interrupt, but are you nearly through? Could you wrap up your remarks?
MR. ALCORN: Yes, sir. Today you debate the sanctity of human life. Humanity has always faced grave consequences when we have had the arrogance and suicidal audacity to do so. And I would end with a quote from Shakespeare, paraphrase: "Hath not a consumer eyes, hath not a consumer hands, organs, dimensions, sense, affections, passions, fed with the same food you are, hurt with the same weapons, subject to the same diseases, healed by the same means, warmed and cooled by the same summer and winter as you? If you prick us, do we not bleed? If you tickle us, do we not laugh? If we poison us, do we not die?" Thank you ladies and gentlemen.
DR. SHAPIRO: Thank you very much and thank you for coming such a distance to speak to us. I very much appreciate it. The next speaker is Miss Kathy Mannion, Fort Washington, New York.
MS. MANNION: Good morning, everybody. My name is Kathy Mannion and I'm here today to represent two of my children who are incapable of representing themselves. My son Brian, age 9 and Daniel, age 8, have autism. Their younger brother Patrick, age 7, has been diagnosed with Asburger's Syndrome. Their older brother Michael, age 11, is a perfectly healthy and normally developing child. Living with autism is typically a life-long struggle for both the child and the family. Children are unable to communicate and have great difficulty understanding language. They are unable to learn even the simplest of things on their own. They engage in ritualistic, often bizarre, sometimes violent and even self-injurious behavior and they require constant supervision and teaching. For families like mine, life is often something to survive rather than to be enjoyed. Autism is not episodic; there are no periods of normalcy. It is indeed constant. My purpose for being here today is to convey to you the tremendous need for ongoing and scientifically sound research in the field of autism. Although the vast majority of persons with autism would be considered incapable of ever understanding or providing informed consent, good, ethical, humane, scientific research has yielded very promising advances in the treatment of childhood autism. But this is only because their parents and guardians have been free to allow them to participate in such research. I learned many years ago while working at Memorial Sloan-Kettering Cancer Center, that whenever there exists a condition for which there is no known physiological cause or cure, desperation and vulnerability pave the way and create a haven for pseudoscience. This, in fact, is true in autism. It is a field that is littered and, in fact, dominated by pseudoscience. The presence of ongoing and scientifically sound investigation is sorely lacking and the absence of the dissemination of accurate, scientifically validated information has not only allowed pseudoscience to flourish, but to prevail. When we first entered the world of autism, my husband and I were not at all prepared for the complex maze that we would have to navigate in order to get an accurate diagnosis and timely and effective intervention for Brian, and later Daniel. They were evaluated by a vast array of professionals and were labeled speech impaired and language delayed. The unanimous recommendation was for both of them to be enrolled in early intervention programs. Although they began intervention at less than 2 years of age, they made little, if any, progress in the first 3 years of their remediation. During this time, my questions and our decisions were governed by what I knew to be true in medical science. When I asked about a definitive diagnosis, we were told that we could not get one. When I asked what the research indicated on types of interventions and their effectiveness, we were told that there was none available. The more I pushed for answers, the more frequently I was referred to various support groups. It was my experience that in the field of mental health, the focus was more on helping parents to cope rather than helping them to find the information they need to make informed decisions about the best possible care and intervention for their children. It took three years to finally access what scientific investigation had already proven to be the most effective intervention for children with autism. Once Brian and Daniel began to receive it, they not only began to learn, they began to thrive. Had it not been for science, I don't know where they would be today. Because of pseudoscience, I will never know where they could have been. Brian and Daniel and countless of other people with autism will probably never have the cognitive ability to provide informed consent to any type of scientific investigation. If parents and legal guardians do not have the right to provide consent for them, people with autism will be almost categorically deprived of the benefits that scientific research provides. However, scientific investigation is the only hope that people with autism have. Without it, they and their families are doomed to a life of agony and significant disability. As a parent, I applaud your efforts to protect the rights of those who are incapable of protecting themselves. I would respectively ask, though, that the committee give careful consideration to autism and developmental disabilities like it where there are no episodes of normalcy, and informed consent could not ever be granted unless by parent or guardian. Without this proviso, scientific study in this field can be virtually eliminated. I ask that in your efforts to protect our children, you do not unintentionally deprive them of the one and only hope that they and their families have for a better life and a brighter future. Thank you.
DR. SHAPIRO: Thank you very much and once again, I very much appreciate you being here today. The next speaker is Jacqueline Shannon, President of the Board of National Alliance for the Mentally Ill.
MS. SHANNON: I'm a little shorter here. Dr. Shapiro and NBAC Commissioners, I'm Jackie Shannon of San Angelo, Texas and I'm president of the board of directors of NAMI, formerly the National Alliance for the Mentally Ill. As you know, NAMI is the largest grassroots organization of people with severe mental illnesses and their families in the United States. We presently have 185,000 members and 1,300 affiliates all across the country. You may be interested to know that all NAMI board members are either consumers or family members, and we represent the many diverse viewpoints of our membership. I myself am the mother of a son with schizophrenia, so I know firsthand what a devastating illness schizophrenia is and what it can do to consumers and family members. I also know that research is very important and it is so for consumers and their families. I am here today to express NAMI's support for many of the recommendations contained in your draft report. I must express, however, NAMI's concern that at least one of your recommendations may pose significant and unnecessary barriers to vitally important basic research. And I believe this was already mentioned by the APA. As you know, NAMI has been a long-time supporter of research and research funding by the Federal Government. And we've also supported two privately funded research organizations, the National Alliance for Research on Schizophrenia and Affective Disorders, NARSAD, and also the Stanley Foundation program of the NAMI Research Institute. Our members know and we well understand that research represents the best hope we have for treating and eventually curing severe mental illnesses. At the same time, though, we understand the vulnerabilities of people who participate as human subjects in this research on severe mental illnesses. Thousands of NAMI family members have participated in research and continue to do that today. Not only to gain possible access to cutting edge treatments, but also to assist in learning information that can benefit other people with severe mental illnesses in the future. We understand that many people with severe mental illnesses are perfectly capable of making their own informed choices to participate in research. But we also know that the symptoms of schizophrenia and bipolar disorder and other brain disorders may, from time to time, impair the ability to make informed decisions or to balance the potential benefits and risks of specific research protocols. Over three years ago, in fact in February of 1995, after extensive debate and consultation with scientists, bioethicists and others, NAMI became one of the first national organizations to adopt a policy which sets forth recommended standards for protecting individuals with severe mental illnesses who participate as human subjects in research. In fact, Dr. Adil Shamoo, a member of the NAMI board at that time, played a key role in the development of this policy, along with Laurie Flynn, Jay Rock Johnson, a current NAMI board member and the former chair of our consumer council, and Ron Hamburg, NAMI's legal director. And if you are interested, a copy of this policy is available on the table outside this room for those who wish to examine it in greater detail. We're pleased that your draft report contains a number of recommendations contained in our policy. For example, the recommendation that all IRBs which review and provide oversight over research involving people with mental disorders as human subjects should include members with firsthand knowledge about these disorders, including people with severe mental illnesses and their family members. We view the ongoing participation of consumers and families in review and approval of research as the cornerstone of a partnership that affords protection for human subjects. And we're also pleased that your draft report recommends that independent assessments of capacity monitoring of research subjects occur throughout the research process. This is very important. And this was also included in NAMI's 1995 policy. As is your recommendation that participants in research be free to withdraw consent at any time in the process, with or without a stated reason. And finally, we're pleased that the NBAC report emphasizes the importance of affording individuals who benefit from experimental medications the opportunity to continued access to these medications after research protocols terminate. We've had a number of such studies in Texas, and that's been a very important issue, that consumers are able to continue with these medications. We're very proud that NAMI's work has provided such an important impetus for your own work. However, I must emphasize NAMI's concern that the NBAC report potentially jeopardizes certain types of essential research by recommending only two classes of risk: minimal risk and greater than minimal risk. For example, basic research involving relatively low-risk procedures such as PET scans, MRIs, EEGs and other imaging studies may be precluded under your approach because these procedures are typically classified as greater than minimal risk. We have continually urged that you apply an intermediate category, which would be minor increment above minimal risk to research of this nature. However, since you have chosen not to do this, we recommend an alternative that you might delineate a list of your research procedures involving scanning and imaging techniques in your report that should be classified as minimal risk. Otherwise, despite its numerous positive recommendations, it's going to be very difficult for NAMI to support your final report. We cannot afford to erect unnecessary barriers to low-risk but vitally important research. And today, you're putting the final touches on a report that will impact significantly on future research policies and practices. I urge you to make sure that what you put forward is properly balanced. That no individual suffers unnecessarily while participating in research. But also, so that a healthy climate is maintained to allow critically important research, our best hope to proceed. And in closing, I want to reiterate how honored I am to have the opportunity to speak to you as the president of the nation's largest consumer and family organization representing individuals with severe mental illnesses. And let me also emphasize of how proud NAMI is of the selection and ongoing participation of Laurie Flynn as an NBAC Commissioner, and we're also very pleased that Trish Backlar, a member of the NAMI family, has contributed her considerable wisdom throughout the NBAC process. And finally, let me say how confident I am that progress, both in research and in research protections, will assure that future generations will not have to endure the suffering that my son has. And thank you very much.
DR. SHAPIRO: Thank you, and thank you very much for being here today.
PROF. CAPRON: Would you entertain one question? You indicated your suggestion that a list of research procedures involving scanning and imaging techniques be classified as minimal risk. In our discussions, we have tended to think that whether the risk was minimal or not might depend upon other aspects of the study going on and the category of patient or even individual characteristics. If our procedures were to allow that to be taken into account, would it meet your concerns? Or do you really believe that procedures can be categorized as minimal or not, regardless—
MS. SHANNON: There are certainly a number of procedures that could be categorized as minimal risk. Of course the best approach would be to have a three-tiered process.
DR. BRITO: Just one quick question. I'm just curious, out of your own experience, when we were discussing defining the two categories or three categories of minimal risk, one of the issues that comes up is psychosocial risks. And in terms of procedures, what is your experience in terms of psychosocial problems experienced by people with severe mental illness when exposed to certain procedures? Or is that a concern?
MS. SHANNON: I'm not quite sure I follow you. Psychological risks?
DR. BRITO: Right.
MS. SHANNON: I don't know if I have an answer to that.
DR. SHAPIRO: Thank you. This next speaker is Dr. James McNulty, Treasurer of the National Alliance of the Mentally Ill.
MR. McNULTY: I'll do my best, but I do have to correct one misapprehension that I'm a doctor. I'm also not a doctor, but there are a lot of them in the room, so I feel like we're in good hands. I have some prepared remarks, so if I do have to leave before I'm done with them, please feel free to grab them. I have to respond to a couple of issues that have come up in the testimony of other people, some of which I found very profoundly moving and affecting. I would also like to state at the outset, however, that I dislike the implication that I've picked up today that people like myself who are consumers—I suffer from bipolar disorder—are unable to act in our own best interests or out of a sense of altruism. And whether you realize it or not, that is a message that I have been picking up in many of the discussions that are taking place here today. I did like Ms. Charo's suggestion of a broader interpretation to consent, and that in fact is something that I've done myself in my advanced directive for health care or I've directed that I would be willing to participate in various forms of clinical research. My record in the past indicates that I've participated in double-blind placebo drug studies, as well as lithium trials to determine the difference in effectiveness between lithium and depecote on the treatment of bipolar disorder. Now I'll proceed with my prepared remarks. I come before you today representing several viewpoints that I hope you can keep in mind as you move toward adoption of your report. I am president of the Manic Depressive and Depressive Association, known as the MDDA, for short, of Rhode Island. I serve on the board of directors of NAMI and I also serve as an IRB member at Butler Hospital, a psychiatric hospital in Providence, Rhode Island, where research is conducted in association with the Brown University School of Medicine and with other institutions. Behind all this, and the main reason for my involvement in these organizations, is the fact that I do live with a diagnosis of bipolar disorder, a disease that I have learned to manage thanks in part to the expansion of medical knowledge over the last quarter century. One of the reasons I came to NAMI in the first place is NAMIs long history of advocacy for research into the causes and treatment of serious mental illness. Having at one time been homeless and without much hope myself, I know the hope that research presents to those of who experience these illnesses and to our family members. In the end, it is biomedical research that will bring us to the point when we can truly say we have conquered mental illness. This is, of course, true of many illnesses, but it is a particularly important point to bear in mind as society becomes more comfortable with the understanding that mental illnesses are indeed physical diseases and disorders. My work the MDDA and with NAMI brings me in daily contact with many other people with psychiatric diagnoses. Among other things, I facilitate peer support groups attended by others with bipolar disorders and other psychiatric disorders and have done so for over 10 years. I'm very familiar with the hopes and concerns of those who attend. You will have to believe me then when I tell you that the foremost complaint coming from people with bipolar disorder that I know is that there are simply not enough effective treatments for this illness. There are only two medications that have been approved by the FDA for the specific treatment of bipolar disorder. As a NAMI board member, I am proud of the work that NAMI has done to encourage research in this area. Having noted the scarcity of activity in bipolar research, the NAMI Research Institute is developing an extensive bipolar treatment network. At the same time, I am pleased to note that NIMH is acting on NAMI's recommendations to move forward with the funding of more bipolar disorder research. Both efforts hold promise for those like me and I hope set an example for other research funding sources to follow. I've also discussed the need for more research with numerous other consumers from across the country who are involved with the NAMI movement and some who are not. They believe sincerely that far more research must be conducted if future generations are to be spared the pain suffered by so many of us in our struggles with these illnesses. And for many of us who live with mental illnesses, involvement in research programs is perhaps the most significant way in which we find we can make a positive contribution to the society in which we live. We feel privileged that we can act as partners in research in a way that neither doctors nor academic researchers nor our friends or family can. This opportunity to be part of something larger than ourselves is desired by many of us who have so often been beaten down by our illnesses. Many of us, in fact, do this knowing full well that the findings of the research in which we participate are not likely to help us directly. And of course we all participate knowing that there are risks associated with being part of an experiment. The point where the research meets the risk is the elusive quest of this Commission. And speaking as someone with an illness and as someone who has participated in clinical trials, I wish to make it clear that I do find some risk both acceptable and necessary. How am I doing on time?
DR. SHAPIRO: If you could draw your remarks to a close.
MR. McNULTY: I will wrap up then by having laid preface to all of this, I would make the following points. I think there do need to be improvements in the informed consent process, more involvement of families and I think a better appreciation of the ability of consumers to be involved in it. Making clear distinctions between research and clinical care. Affording ongoing access to treatment after a project is done, which is very critical in today's environment of managed care. And I think really involving consumers and family members on IRBs, I would urge this Commission to really make that more of a directive than something that's optional. Thank you very much.
DR. SHAPIRO: Thank you very much for being here. Questions?
PROF. CHARO: You mentioned your participation in clinical trials. I wonder if I might ask you a couple of questions about that experience? The trials that you described are trials that definitely have some risks associated with them—they were drug trials. They also offered the prospect of some personal benefit in case you got a drug that worked better for you. Were you ever invited to participate in research that had no prospect of benefit to you, but had risks that were in the order of what you experienced?
MR. McNULTY: Well, the second study I was on was not a direct risk. One of the problems with bipolar disorder in particular is that we note that medications often stop working for people somewhere along the line. And that's why I got involved in the second study, which is the lithium versus depecote study. But there was some proximate benefit to myself; I have to be honest. I have asked myself the question "would I be willing to act out of a sense of pure altruism?" And my answer is affirmative to that and I offer as an example my Uncle John who died of melanoma, very painfully I might add, and participated in a number of clinical trials until he felt he could no longer live with it, at which point he said "that's it—let me go." And when I thought back to that example, that's more or less what I used in my own decisionmaking framework.
PROF. CHARO: But you've never actually volunteered for such a non-beneficial research protocol yet.
MR. McNULTY: As a member of the IRB at Butler Hospital, I have yet to see one come across that could be characterized as not having direct benefit to the subjects.
DR. SHAPIRO:Thank you very much. The last speaker today is Miss Catherine Klapp, FragX Research Foundation in Massachusetts.
MS. KLAPP: Thank you very much. I am President of FragX Research Foundation, which is a advocacy organization which supports research on Fragile X Syndrome. My two children have Fragile X Syndrome and I started this organization 5 years ago with my husband and we have about 1,000 families now. Basically what we do is support research aimed at an eventual treatment. So must of us feel very strongly that we would like to keep this research moving forward. You may know that in Fragile X Syndrome, like autism, most of the individuals are not likely to be able to give informed consent. My son Andy will never be able to give informed consent. So therefore, it is going to basically be my job to make decisions for him throughout his life and that has been the case so far. I'd like to speak from the point of view of a parent looking at your recommendations and feeling that you may unintentionally throttle the very research that offers us hope. We, if you will, test medications all the time. Andy has quite a bad seizure disorder as part of the Fragile X. This has meant several helicopter trips into Boston and six or seven medications, one after another, all of which so far have failed. The newest one that he s on was not available several years ago when he had his first seizure and so we, it was our own son, are already benefiting from the kind of trials that may not happen if this language goes through. An important point I would like to make about this is that children with Fragile X and other children with disorders like Fragile X, do not respond the way most children do to standard medications. Ritalin, for example, acts quite differently in Fragile X. And this is all lore because I happen to be president of this organization and my husband, as a psychiatrist, has kind of become a specialist in this disorder. We have doctors and parents calling us from all over the country desperate for information on what of the available drugs they can use for Fragile X syndrome and there is nobody of medical literature to help them. There are no double-blind studies but there is lore and the lore seems to work but it s also quite a frightening feeling to be experimenting on your own child. It s just that that s where we kind of are right now and what needs to happen to change that is some good proper studies on children that have the problem that you are trying to address. And in this case, it means Fragile X. It means participating in studies which may have some risk. There is no chance of getting informed consent. I would like to suggest that the people best qualified to give that consent are the people closest to the individuals involved. In this case, the parent or the guardian. If you think about it, in our society, it is the parent or the guardian who has this responsibility for all sorts of other decisions for sending this child through life as positively as possible. And so I m concerned when I see recommendations that some impartial observer needs to be brought in from outside and make this judgment when I really think that it is the parent or guardian that is most qualified and most responsible for making these decisions. So I see it as something of a rights issue. Andy s right to participate. My right to make the best decisions I can for him. Thank you very much.
DR. SHAPIRO: Thank you. I appreciate your remarks. If you would wait a moment there s at least one question someone would like to ask.
PROF. CHARO: I want to make sure I understand where exactly your discomfort lies and what you feel we ve lost. What s been proposed so far would absolutely allow a guardian to volunteer somebody into research that has a lot of risk so long as it also had some possibility of personal benefit.
MS. KLAPP: That s what concerns me and in an effort to keep remarks short, I didn t elaborate on that, that I think it is very hard to prove in any given study that that study could have direct benefit to the individual involved. Now in the case of a seizure medication, it could have direct benefit. However, as president of Fraxo, we are also supporting team therapy and demethylation studies and so on and so forth, and those are studies that are directed at what is close to a cure. And participants in those studies may have no immediate benefit to gain from participating even though there may be some risk. And just as the previous speaker said, that he would make the choice, an altruistic choice, to participate when he knew he had nothing to gain. In this case, I need to make that choice for Andy and I feel that I m the one who s best positioned to do that. And the truth is that I already do make those choices when I, you know, get us into the newspaper and tell them that my daughter has Fragile X and therefore label her as a mutant when she has no symptoms. I have made a choice that may hurt her because it really needs to be done otherwise we re just not going to get anywhere, and I, so I m really very concerned that we are not going to be able to progress past the stop gap, seizure, Ritalin, sort of measures to something that really could help.
DR. SHAPIRO: Thank you very much. I very much appreciate you being here. We re going to recess the meeting now. Let me suggest that we try to reassemble at quarter after one. Steve, you have a group that you have to somehow mobilize and maybe you can do that around one.
DR. SHAPIRO: Pick up some additional copies in a few moments to pass out to interested people, but Steve, due to time, why don t we get started.
MR. HOLTZMAN: Sure. We were asked to look at the question how would we deal with recommendations effectively 8 leading up to 12 and the conceptual organization of them. If you look, 8 started out with the research that presents greater than minimal risk and offers the prospect of direct benefit and that was the general category of recommendations 8, and 9 and then we went on to 10 and 11 where there wasn t a prospect. So the flow chart in front of you really suggests how we reorder a bit our thinking, and that we start with the global category of greater than minimal risk, put aside for the moment whether there is prospective benefit. The first question that seems to be at stake is, is the subject capable of consent, yes or no. If yes, then after they have given their consent you can do the research. If they re not capable of consent, the next question is, did they give prospective consent to the protocol and if you look in Recommendation 11, there seems to be some ambiguity: 11a represents the prospective consent as being to a type of study, whereas 11b talks about changes in the specific protocol and it seemed to us that if we re going to keep intact the concept of consent, let s keep it full-blooded, that it should be prospective consent to the protocol that s in question. I ll come back to why we think that s okay. If there has been prospective consent to the protocol, again where we are dealing with someone who is not capable of concurring consent, then you can go ahead but there has to be a role for the LAR to monitor what s going on. On the other hand, if there wasn t prospective consent to the protocol, now you conceptually move down to the question is there the prospect of direct medical benefit. Eric, could you push that up now? So, if there is a prospect of benefit, and here again we are in the absence of consent or prospective consent, then you can go ahead with the research if the LAR approves and here, Alta suggests that we flesh out our expectations of the LAR. That the way they should be thinking is if there were previous general expressions of desires or wishes, not to a specific protocol but to a type of research, that would be taken account of. Failing that, move to another standard of the best estimate of the subject s wishes based on the knowledge of the subject and then last, in general, best interests, presumably because there s a prospective benefit. And, once again, the LAR should monitor. Now, it s only then we move on the other side of this. Well, what if there isn t prospective benefit and then we land at Recommendation 12.
PROF. CAPRON: The question for clarification under LAR approves, and this was I thought the point that Larry, same kind of point that Larry had insightfully discovered and I think that you may have all— DR. MIIKE: I stumbled on it.
PROF. CAPRON: No, no. And they may have all stumbled off of it. Are we saying that, in what sense other than the language, is there any priority to these three that are listed here because, if, you could always go with best interest.
DR. MIIKE: I think we meant that it is sort of sequential. If there was a previous expressed wish then we would pay attention to that. If not, then the best estimate and then finally the best interest.
PROF. CAPRON: But I guess my point would be we usually conceive of this as a situation in which we are merely giving guidance, for example, around end-of-life decisions, if the wishes are known. In some jurisdictions, the decisionmaker can t act unless the wishes are known by clear and convincing evidence and so forth. But where there s a best interest alternative, the reason for going with the other is that that ethically is what accords with the notion of a substituted decisionmaking process. But other than the relatives all aiming for that, there s really no enforcement process that pushes anybody toward that. I mean, the courts don t see most of the cases and the IRBs aren t going to see most of the cases. I m not objecting to the notion that we would expound in favor of this but this seems to me to be something that would not be in the recommendation as such.
DR. MIIKE: It s not.
PROF. CAPRON: I thought this was all going to be you do this and then you do this and you do that and it seemed—
DR. MIIKE: We also talked about we ve got to keep our recommendations fairly short and simple.
PROF. CAPRON: So this is merely descriptive of what would be the ideal; that when you do know what the person wanted, you ought to decide that way. If you know, as Bette was saying, a lot about someone, they d never express wishes on this, you do that and when you don t know, you go with best interests. Okay, so that s fine. But we re not saying that anybody is in any position to actually regulate this other than on good faith.
DR. DUMAS: I have a concern about prospective consent to a current protocol and it would make me feel better if we called it prospective consent to research related to the protocol because, it s conceivable, that the patients might be recruited for a projected that was not anticipated when they gave their consent so it might not be to a particular protocol but to research that s relevant to the protocol.
PROF. CHARO: I d like to speak directly to Rhetaugh s point because it s related, I think, to the question of the language of the LAR and it s related to Larry s first point that he so elegantly captured. What s been drafted is the following kind of image of events. People give informed consent to very specific things that have been specifically described. Now they also say I want to be put into research that involves MRI but don t put me into research that involves spinal taps. The research protocol that comes down is one that has to deal with PET scans, neither MRIs nor spinal taps, we have no specific direction. What this then says is that their representative is supposed to use everything that they have to develop their best estimation of what this person would have chosen under the circumstances and to effectuate that person s genuine wishes. And in this way, you can give consent to very specific things, but all the other statements you make about research that s related to but different from the one that is being proposed, etc., is in the use of the LAR, it s in the LAR s hands to use when they try to figure out if you yourself would have volunteered if presented with this option. That s the image of how this would work.
DR. DUMAS: It seems to me that would make me feel even stronger that the consent that s being given is to research and not to a particular protocol.
DR. MIIKE: I thought what you were talking about was the right arm that said yes to the question. What Alta was responding to was it gives guidance to the LAR in case there was no consent. And I feel as though that one cannot say that we can go down the right arm saying yes there was consent if there s this general notion that they consented to some kinds of research rather than something more particular like a protocol. And the way Alta has defined protocol is fairly liberal. It wasn t what I m thinking but I can accept that definition. I was thinking of a specific study but I can accept what Alta is saying.
MR. HOLTZMAN: I should say that I was using shorthand by protocol up there simply to distinguish it from some sort of broad of idea of "I m in for research." And that if you look again at section 11 when we talked about approval of types of research and then we started talking about specific protocols, there seemed to be an ambiguity, at the least, between of how we seem to be thinking in Recommendation 11.
PROF. CAPRON: So now we re using the word protocol in two ways. Most of the time in this report we say an IRB may approve a protocol. What we mean is a research plan for this research. You re now using the term here and maybe we should use a different term. Steve. I m addressing Steve. Was using the word protocol playing off of what you said Alta to say a protocol is a category of intervention. Is that right? To say MRIs but not spinal taps? Let me first ask Steve what he means and then we can decide. That s what I was asking. And then we can decide whether we want this word or another word but I think it is a critical issue.
DR. SHAPIRO: We better stop on it and decide, and I think Tom is eager to make a comment before you speak, Steve.
MR. HOLTZMAN: Let me phrase the three options in front of us with respect to what we are calling prospective consent. It s either narrowing to a specific protocol where one can envision all of the risks and benefits, and the objective of the research. It could be something somewhat broader than that to what we call variously a type of research, all right? Or it could be even broader than that. What I think we were thinking of or what I was thinking of here is that there has to be a certain narrowness for it really to be consent and since the backdrop we re going to be deferring or have this potential to go down to the LAR approval that it was better, in my mind, not to weaken the concept of consent. Keep it narrower; how narrow I m not—
DR. SHAPIRO: Let me just make sure I understand. You in your own mind are uncertain between the first two possibilities, or against the third possibility but you re uncertain. Let me just ask other members of that group who got together what their sense of it is before we see what other Commissions have to say. Alta.
PROF. CHARO: My sense of it was that in the prospective consent we were talking about consent as narrow and specific as consent that is given concurrently, no distinction. Take a particular protocol as to the way the word is used in an IRB review, but of course, very rarely are people going to be in a position to give consent to a particular protocol. So what is going to happen is that all the rest of the stuff that they say about how I m willing to—this might be where I might have confused you—if they say yes, I d be willing to have MRIs but not willing to have spinal taps or I d be willing to have bladder muscle biopsies but I wouldn t be willing to have open heart surgery. All of that stuff is what gets fed into the third-party decisionmaker. It s not about consent. All that is about quite controlling guidance to the third-party decisionmaker. So there should be no loss.
DR. SHAPIRO: You put in a new word. Controlling guidance.
PROF. CHARO: Well, didn t we say that they are supposed to do what the person would have chosen to do so if the person said I do not want certain things that they are not going to be enrolled in certain things?
DR. SHAPIRO: Let me—before we get down to just leeway, or lack of leeway, the LAR has, I want to stick on this informed consent issue at the top of this tree or towards the top of the tree. I understand what you just said about the things, informed consent as we normally think of it. What would your view be about what we should do with this if someone had said, executed a document, that said I want to participate and lists a fairly lengthy list of things that they re willing to participate in which characterizes it in various ways, I don t know how to characterize things. What standing would that have in this area? Would it lead to the yes or to the no? I just want to know what s on your mind. I m not suggesting.
PROF. CHARO: It would not be consent but it would certainly still permit their representative to say this person would want to be involved.
DR. MIIKE: So it would go down in the no category.
DR. SHAPIRO: Unless it s protocol-specific and the way we talked about it throughout this report, I m just trying to clarify what you think on that or what any of you that are drafting this think, it would go down the no branch although Steve is a little uncertain about that. Right, Steve?
PROF. CHARO: How could you be uncertain? I m the one that wanted the blank check and you talked me out of it.
DR. MIIKE: In the past discussions that we ve had about what it means to have prospective consent, I seem to recall we even were talking about really the potential enrollee in our experiment, had been talked to about that experiment either by the investigator or other. So it was very specific.
PROF. CAPRON: This is the kind of thing that can only be done when you are in this stage of your illness. At that point you won t be able to give consent. We wouldn t want to enroll you, however, unless you d agreed to do it, so let s talk about it now. So it s a limited type of research. It wouldn t even probably be someone who is in the early stages of Alzheimer s saying something because the research that would be done in four or five years is not likely to be describable exactly today. Is that all correct? So, it s a very limited, very, very limited view.
DR. SHAPIRO: Well, I think we need to discuss that issue because I think it is a very important issue and that is and let me just characterize this as the view of this group although you may have some differences between, among you as the case may be—that under this, if you just look at this framework, which I think is a decent, useful framework which will lay out the recommendations that perspective consent in this tree, I mean it is reading to a specific protocol and it s that, the answer s yes, okay. If it s no, then it s in the LAR s hand. What to do subject to what everyone might want to say about the LAR. So that means, in this case, that greater than minimal risk where consent is not available at the current time and no prospective consent in the same sense of the word has been given, then it s the LAR who makes the decisions. That s what this says. Let s have some comment. I m sorry. Did I misstate it?
DR. MURRAY: Where this scheme makes the biggest difference and I may just—tell me if I ve gotten the facts all bollixed up but an MRI, where the person has said in general I think that once I am totally unable to consent, I have no objection to your study. I would be happy to have studies done like this but an MRI is regarded as greater than minimal risk. And, in this case, there s no potential benefit to the subject but they have consented to this specific protocol. That takes you down to the lower right in the box that says you can t do it.
DR. MIIKE: Yes it does. Greater than minimal risk. They gave a kind of general consent, in fact, enthusiastic general consent but they didn t say yes to the protocol and there s no benefit to the person, that s a no.
DR. SHAPIRO: Maybe you got a special dispensation.
MS. KRAMER: No, I just, I just am confused. I want to make sure I understand this. So you re saying it s okay if it s protocol-specific, the LAR now. The LAR has discretion over protocol-specific, types specific but not research in general. In other words, you re denying that blank check.
DR. SHAPIRO: If I could just, I think the issue with the LAR or just not at all really has to do with prospective benefit. So if there s a prospective benefit, all this leads to the LAR.
MS. KRAMER: Right, exactly. But I m saying then over what kinds of decisions does the LAR have jurisdiction? And, if I understood Alta correctly, or the group correctly, they said the LAR could consent to a specific protocol. Could consent to a specific type.
PROF. CAPRON: No, no. The LAR steps in to give permission in lieu of consent once a specific protocol is up. The other categories were all in the early stages.
MS. KRAMER: No, no. I realize that. But I m saying in terms, in terms of assessing what might have been the expressed or generally expressed or generally filed to a best estimate, best interest of the subject. That they can make a decision within those interests on a specific protocol or a specific type of research but not research in general.
DR. SHAPIRO: Could I help out here? I think they can make a decision for any protocol that comes along that satisfies this.
PROF. CAPRON: It has to be some specific protocol when they make their decision. And they can draw on those statements that weren t precise enough to be consent to a protocol but which are good advice for them. We still haven t gotten to Alta slipping the word "controlling." That those advisees are controlled.
DR. SHAPIRO: But let s see what others have to say. Look, let s, there are lot of people that want to speak but I would really like to see if there is some, give some time to people who have some trouble with this as opposed to people who think it s a wonderful idea. Bernie.
DR. LO: I continue to be troubled by this type of research that does not offer a real prospect of benefit to that individual but offers the promise of really important understanding in the condition. It is not minimal risk in any plain meaning of the word and no one seems to like the idea of it just a little more than minimal risk, but we foreclosed that here except for this number 12 bypass. If a person, while still competent, says you know, I went to all those NBAC meetings, I read their reports, I understand their concerns and doggone it I really want to be able to be in a study that helps other people. I m willing to have a spinal tap or I m willing to have an MRI scan or have a PET scan. That was allowed under Recommendation 11 in the, as I read it, on page 140 and now this scheme forecloses that. And I think that we re saying that this option 12a, 12, and I m just really concerned that anything that takes it out of the decisionmaking capacity of an individual that s still competent to have a say and groups it into a secretarial commission or a special IRB mechanism is a very, very different kind of procedure. And, I m just, I m just disturbed that there s this type of research that on some intuitive level, I think, many people feel is very different than the kinds of challenge studies, drug holiday studies, that we were talking about as being very problematic and yet we re foreclosing it here even if the patient, as best as you can anticipate what a protocol is going to be a couple of years in advance, or six months in advance. We re saying, no, it s not going to work in this.
DR. SHAPIRO: Let me just say that on Bernie s reference to Recommendation 11, what distinguishes that recommendation from this and the context of Bernie s concerns is "A" under 11 talked about type of study as opposed to particular protocol. So it does make a big difference which way you go at it and we re going to have to decide which way we want to go at it. I m sorry. Larry then Eric.
DR. MIIKE: You know, our presentation is incomplete because we haven t talked about Recommendation 12. And it just depends on whether, what side you re looking at that at. Are you looking at 12 as a really big, huge hurdle and only can be done at the secretary's level or are we talking about a modified waiver process, which makes it a lot more flexible which I think some of the kinds of things we ve been discussing by e-mail, the alternative 12a, some combination of 12 and 12a. But if we allow some general notion or some general statement about future research, then we re making it easier to enroll people in with a lesser consent than I would give to some other research. So it just, it just does not seem right to me that we loosen that in those areas where it s saying greater than minimal risk, no benefit, and we make it easier to enroll them with a much lower standard of consenting than I would be in the similar situation. That s why we have this dilemma, because we ve tightened up 11 in terms of the meaning, the definition of actual consent. Really the proof of the pudding is that what we are talking about is a rare exception, or are we talking about a much more reasonable alternative to enrolling people into these experiments which has greater than minimal risk and no benefit?
DR. SHAPIRO: Let me just say something before turning to Eric. Obviously, these issues are interrelated, as Larry just indicated, and so whatever way we go at this, we have to circle back and look at them together at some stage and so we will certainly do so. Eric.
DR. CASSELL: I share Bernie s concern on the one hand, and Larry s concern on the other hand. Why should it be easier for somebody to consent at this stage than it would be if they were right there and competent? It doesn t make sense to me. On the other hand the need for the kind of research, moving that forward, is really there. For myself, I see a mechanism of making this more public. I think the secretary mechanism is clumsy and people will shy away from it. But there are such things as registries. Every time an IRB does something like this it goes into a national registry of research protocols that have been handled this way so people begin to get a chance to see what actually is transpiring and see what happened with them. I m not sure how you get into that yet but I think we can walk ourselves there because I m convinced also by the testimony and by my own experience. But we have to find a way to get some of this to go forward without it being licensed injured.
MR. HOLTZMAN: To your part, Bernie, and you know from our discussions that I share a lot of your sentiments, the concern, I think, is with the mechanisms down in the lower right hand corner of the no box. Okay? I think we all agree that the number of people giving broad-based prospective consent or narrow-based prospective consent is probably pretty small. So that s kind of, at least for myself, very simple-minded; I like to try to keep certain concepts clean. I think informed consent has a very important role in being kept robust and clean and that is why, with Larry, I would like to keep it consistent with our concepts of informed consent but then deal with the issue below in the lower right.
DR. LO: Well, then I think it s, a number of us have said throughout the day, it becomes crucial how we deal with that issue since you extended that—I mean, I agree with Larry and Eric. I would like to find a feasible, pragmatic way to allow these stages to continue and also protect subjects.
DR. SHAPIRO: Let me make a suggestion now in view of where this discussion has gone. Let s turn, without having resolved this or indicating any full acceptance of it, although I think myself it is extremely useful, let s go to 12, which 12, in this case 13, is just sort of a follow- on of 12, really attempts to deal with that lower right hand corner however you get into that corner, whether through this mechanism or some other mechanism. You know the Recommendation 12. First of all, let me say something about the Common Rule. I don t think we should worry ourselves with. Do we want to amend the Common Rule or change a subpart of the Common Rule, we need language that clearly what we re getting others to think about and they ll figure out what the best way to go at it is whether it s a subpart of the Common Rule, or the Common Rule, amendment of the Common Rule itself. Let s just put that aside. Recommendation 12 was designed initially and is designed to try to make this waiver process something more real in some sense, well used, than has been the case in other areas where we also have this capacity to sort of appeal to the Secretary of HHS wherein the current regulations are very seldom used because this procedure is a very difficult but not impossible process. So it s just as if, almost as if it s not there. And this original recommendation here was to try to make that more available by having OPRR establish a panel which would adjudicate on these matters on behalf of the Secretary. And also by e-mail we sort of suggested yet another alternative which either could be combined with this one or replace it altogether and that was the recommendation which I think you all either have copies of or had copies of, apparently, it s at your places, which essentially says, and I can t get all the language straight without reading it, but in cases which were described as compelling regarding the cost, the benefit and risk ratio, that the IRB could if it engages in public disclosure approve such proposals. And although the way it s written here, it says, it can see protocol, permit interested individuals in groups to express their views and then it would publicly sort of indicate what in fact it decided. My own view was that this was an interesting thing to consider, although now that I look at this carefully, I would rewrite it somewhat when I think they ought to inform the sponsor, whoever that is, because they may have an interest in it and that should be specifically mentioned. But, it s, let s not worry about the exact wording here for the moment. It is another way of dealing with that lower right hand corner Eric talked about a moment ago or that Bernie was concerned about. And indeed, it will be possible if it was your wish to in some sense, give the IRB a choice of what it wanted to do. Those IRBs who felt comfortable going ahead and approving it and publicly disclosing it and so on could do so. Those IRBs that for whatever reason they had, didn t want to do that could use the panel but there are mixes and matches here. There are various alternatives here. I don t know that I understand myself which would be the best but let s just use this as a starting point to see what other kinds of ideas come up and what people like and dislike about all this. Alta.
PROF. CHARO: I d like to speak in favor of a somewhat more liberal version of 12 in terms of the way the recommendation is written, although the key elements are in the text. I d like to speak against 12a. It makes me very uncomfortable and I would like to recommend finally a third aspect to this which has to do with putting more meat on the bones of our understandings of minimal risk, which may clarify some of these debates for people. On 12, the recommendation in the bold type, although it does not say what is in the text but I think is essentially to its efficiency and its political legitimacy. I think it s important that we understand that this body that we re proposing as a standing body not simply be there primarily to be a case-by-case appeal for particular protocols that don t meet the recommended regulations, but that it actively see its rule as proactively outlining classes of research, type or whatever we re doing, particular interventions, particular kinds of studies that are usually appropriate for an IRB to waive, usually appropriate for an IRB to approve despite these regulations and issue this guidance to IRBs and move then to the IRBs the day-to-day responsibility for approving those studies. I don t want to see them just as a single protocol appeal board, but really much more prospective. And second, not in the bold, is the fact that the membership of it has to be quite representative on the consuming end, the subject end, as well as the research community to give it the legitimacy to go ahead and essentially authorize research on people who can t consent for themselves in situations where there s no benefit to them.
12a, which is basically a mechanism that presumes that enough sunshine on research will ensure that it s done in a way that is ethically appropriate, concerns me enormously. First, I m not convinced that you can actually achieve that degree of sunshine. We are watching IRBs struggle with it in the emergency research waivers, which I will remind people waivers that are given only for research that is potentially beneficial not without any prospect of benefit. Second, most of the people who are going to be seeing all the details about this research are not people who are personally implicated. They ll never be at risk of being enrolled in research like this and so don t necessarily have the kind of self-interest that you need to have to have kind of a full-flavored evaluation of both the risks and the benefits and whether or not it s justifiable. And third, to the extent that there is any degree of prejudice against the population of the mentally ill and in this case, I think I am really specifically talking about the mentally ill and not impaired decisionmaking people in general. There s a possibility of a great deal of lack of empathy among people who hear about the research. So, I m skeptical about the use of sunshine and politics as a kind of protection against abuse as a mechanism. Finally, I think an awful lot of the reason why there s a lot of pressure on these recommendations that are on box 12 is because of our lack of clear understanding about what constitutes minimal risk and a large, in fact, the vast majority of the examples given to us so far in research that might be hindered substantially is research that s right on that borderline. The PET scans and the MRIs and the genetic pedigree studies, the bladder muscle biopsies and spinal taps. Those were the 5 that we got in a memo today, and it strikes me that there is good data in the literature on the frequency of adverse events of every type of each of these things. We know how many people died per thousand. How many people have permanent disability, temporary disability, etc., and that it is probably time to start adding some quantification to the notion of minimal risk. We know that we can have some quantification on daily life risk. I sent an e-mail around with some of those statistics and as a third matter that I d like to direct, I d like to recommend that OPRR be given the resources to actually try and add some quantification of the notion of minimal risk and begin to issue some definitive guidance on whether or not these particular kinds of procedures are usually eligible for minimal risk with an IRB, of course, always checking that the particular population is not unusually vulnerable, and maybe find that there are far fewer areas of research that will be hindered by our proposals than people are speculating because we d achieve some clarity here.
DR. MIIKE: I think this is an area of how we present it is going to be important. So I would look at that last leg on the right side that says no and really put a positive emphasis on, not present it the way we do now which it just says no, except you might appeal to the Secretary. It would say that if there is really no individual either the prospective participant or his or her legally authorized representative, I feel much more comfortable that we have a processing place for making those decisions rather than leaving it up to an individual. So, the way I would present this and say exceptions allowable by the IRB and not talk about the Secretary but the IRB to follow standards of guidelines or whatever that would be issued at a more national level so there s consistency so that we can combine all of the suggestions that we ve made, including our registry so that, and it seems to me that we can also have those guidelines include addressing the notion about those little things that are a minor, I don t know what a minor increment is but, in the guidelines they could talk about how that notion of a graduated risk can come into the decision of about how waivers may be made or not without us getting into this sinkhole of having more than two categories of risk.
PROF. CAPRON: I agree with Alta s sense between 12 and 12a. I agree with her suggestion that this we ought to move forward to put meat on the bones and I wanted to respond to Bernie s earlier comments because the language in 12 and on page 142 came out of an e-mail exchange of Alta, Jim and I and one thing we didn t include there, Bernie, is the willingness to approve a project where one has subjects who have expressed exactly the kind of generalized preference for contributing to research knowledge and being involved in certain kinds of studies, something which we just ruled out as qualifying as consent to a protocol but which, it seems to me, in that review process of something that ends up facing the no and therefore being in this category 12 where that preference of the subject would be very relevant. And if a protocol were designed to draw on subjects who had expressed when competent a willingness to be involved in this kind of research, it seems to me that would be a factor which would legitimately be taken into account in reaching the determinations, because we do anticipate both case-by-case determinations and the development of generalized standards, and I would like to see language to that effect included on page 142 because I think the point you made is a good one and we shouldn t just be throwing up our hands and saying that someone who s taken all the trouble to say I want to contribute to this is someone who is more suitable for that research project than when you don t have that and you want to honor their wish to make that contribution, it seems to me and that could be part of this waiver process. But, it s not there now.
MS. FLYNN: Can I ask, I m troubled by all this. It seems to me it s still enormously bureaucratic and is still very difficult to get these studies done that we re now recognizing are on the borderline but represent a huge volume of the significant research that we want to see. Let me pose it this way. I have three generations of suicide in my family. And let s say that my daughter, who is afflicted with mental illness, has long talked to me about the desire to participate in basic studies that would look at the genetics that may be involved with suicide and she is unable to herself give consent. I cannot, based upon that general, in my own status as her legally authorized representative, because there s no benefit to her in these studies of basic science, I cannot consent to her being a participant in MRIs, in EEGs that we have to go through this cumbersome procedure that may or may not at some point be parsed out, but I cannot as her legally authorized representative, knowing what I know, commit her to a study that does not have direct benefit? Is that what we re saying here? That I would have to go through either this secretarial panel or some other process in order for her, because the study will not benefit her condition, will benefit the greater good for many people, including members of her own family potentially, is only minimally of risk greater than the current standard and involves very commonly done procedures that most people have no trouble with but because she is unable to consent, I can t consent and we ve got to go through this administrative bureaucratic hurdle that may or may not in itself work. Something we haven t constructed so we don t know how it s going to function in the real world. Meanwhile, 10-15 percent of all people with her diagnosis commit suicide and we don t know why.
MS. KRAMER: When we broke for lunch, Alta and I exchanged some conversation really a propos of some of the public testimony that was presented and what became apparent to me was that Alta s understanding of what constitutes "does not offer the prospect of direct medical benefit" to the subject is a great deal more liberal, where she sees that as a more open category than I had perceived it to be, doesn t make any difference. My question is this. I would like to hear a description of what kinds of research do not offer direct medical benefit. We were having the conversation as I said, a propos of some of the testimony that was presented, particularly by the two mothers of young children and I think also by Mr. McNulty and my perception was that what they were talking about would fall into the category of does not offer the prospect of direct medical benefit and yet Alta, if I understood her correctly, was saying to me that there was nothing that they talked about that in fact would be in that category. That everything they talked about would offer the prospect of direct medical benefit. So it may be that a part of the problem that we re having here is that we re not all talking about the same thing so I would like to ask about some discussion or definition of what that is.
PROF. CHARO: My understanding of prospective direct medical benefit is that any possibility of personalized medical benefit qualifies. That nobody who testified, in fact, I was referring to people testifying to a particular study that they wanted to be enrolled in or had been enrolled in, nobody was talking about the studies that are purely informational such as the imaging studies that can offer no possibility of personal benefit to the person who undergoes it. They are purely informational. A drug study, for example, that has a placebo arm means that there is a 50 percent chance you re not going to get any active drug at all. That is still a study that, in the IRB world, is one that offers the prospect of direct medical benefit even though your odds of getting the study drug were only 50 percent and the odds of the study drug will be helpful are as yet somewhat unknown. That still qualifies for prospective benefit.
MS. KRAMER: Well what about the case that Laurie just raised about suicide?
PROF. CHARO: No. Laurie was talking about imaging studies, which may or may not be minimal risk. No, I m sorry, genetic studies which some IRBs continually interpret as being greater than minimal risk and others do not and which can be constructive with lots of confidentiality safeguards. And so again, it s in this, in some ways the problem is really not about, the problem is not entirely about the recommendation to be protective in greater than minimal risk research. The problem is tightly tied to variable definitions of what appropriately belongs in the category of minimal risk research to begin with.
MS. KRAMER: No, no. But I m asking you about that particular study, where in the context does not offer the prospect of direct medical benefit to the subject.
PROF. CHARO: Well, it depends on the study. If they re going to tell her something that might affect her future care, it offers the prospect of benefit. If this was a study that actually could help her, know if she s got a gene that s now highly associated with particular kinds of conditions and it could affect the way in which her own medical care is organized, it would offer the prospect a benefit.
MR. HOLTZMAN: But if it was the original study to try to find the gene there s no direct medical benefit.
MS. CHARO: If it s the original gene they're trying to find, there s no possibility of benefit in the foreseeable future.
MS. KRAMER: Laurie says that she comes from a family where for three generations there are instances of suicide so it s highly suspicious that there might be some genetic correlation. Now, if in fact, if you assume that there may be a genetic correlation, then can t you say there is a potential for direct medical benefit to her daughter from being enrolled in that study?
PROF. CAPRON: Depends on where in the sequence of research findings you are. If you re just looking—
DR. SHAPIRO: That question remains on the table. We ll get to that issue but there are others who want to speak also. Eric. I don t know if it s in response to this or not.
DR. CASSELL: This actually sounds like a discussion in an IRB as somebody tries to move a study from an impossible place to a possible place. We would really prefer that that solution is not the solution to the project in the same way as deciding oh, it has no risk, thus moving the study to another place to allow it to go forward which is what presently happens. We suffer from a couple of things. One is that we have no information about what happens in this set of sites. How many are out there? What s going on out there and so forth? That s why I think that whatever mechanism we come to, there should be a registry. Medicine is full of registries and they work very well. We have tumor registries and special case registries. They re very common things for us and then at the end of the year you ve got some information about what are the kind of cases that people are seeing. But I also feel that what Laurie s saying is correct. I think, it s not a question of feeling. I think what Laurie is saying is correct. There ought to be a way for that study to go forward and yes, she ought to be the one to consent. On the other hand, you know very well, we can take and change the situation a little bit and you move think that that parent should consent because you will feel that that s too much danger involved in that and not enough benefit to anybody but the parent. So, that, that s what our situation is and even if we want to do these kinds of studies, you who want to do these kind of studies, have got to find a way that does not make it so cumbersome, it s moved by going up to the Secretary. That will make it minimal risk and so forth. You ve got to find a way that makes it possible to move forward but isn t quite so cumbersome.
MS. FLYNN: I was going to say, I think that we ve made a lot of this problem by using only the two categories and not defining well what s minimal risk and so if we re going to stay with the two categories, I understand you wanting to stay within those two categories, then what are we going to do about much of this basic neuroscience that is so crucial for all of these brain disorders, all of these people we ve heard. Certainly folks that I deal with see this research as critical and we ve gotten ourselves that it s now special case to do what our, you know, some of the most significant and in some cases, largest studies going on.
PROF. CAPRON: Well, I think we do have an experience in this area and it is the recombinant DNA advisory committee which reviewed and gave advice to the director on protocols involving the use of a common DNA first in plants and animals and then eventually in human beings. And that process, although more cumbersome than just having things reviewed by the local IRB, was not a roadblock. This is an area which, in the view of some scientists, has moved further than the science justifies it having moved. And having sat for a dozen or so years on that body, I will tell you that a lot of protocols came through which were much much better by the time they had been through that process than when they were approved by an IRB to the point that some of them, it was hair-raising to think that the IRB had ever approved them. So, I think that the sense that this body is a roadblock rather than a channel is a misdescription. We can count on it doing things and as described in the commentary on page 142, it is intended that it will through a process, Eric was talking about it as a registry, well everything that comes before this IRB becomes part, as it were, of a registry, develop generalizations. And again, we have that experience with the advisory committee. It got to the point of saying these things, we don t have to look at. We know that they can be done with an acceptable level of risk without having specific review. We ll review the next one that comes along that does something new where there s a question about is this too risky or not. And it may turn out, Laurie, that with that experience, this body will be able to say, MRI scans for people with these kinds of diagnoses are not more than minimal risk and they do not then, just not on an ad hoc basis that this IRB struggling to give the researcher a good day, says yes and this IRB says no, but rather that a standard is established that says that this is or isn t in that category for certain kinds of patients. So I really don t think we should see this as the National Bioethics Advisory Commission is saying you can t do huge areas of research and we re establishing a bureaucratic roadblock.
DR. CASSELL: Then we have to make that clear, don t you think? I believe we have to make it clear.
DR. SHAPIRO: Steve and then Jim and then Bernie.
MR. HOLTZMAN: One question and one comment. The question to Laurie. When you were reciting your case, there were two elements. One was that your daughter asserted an interest in the research and then the second was that in your belief it was really not, there was not significant risk involved. Was your daughter s assertion of an interest really the central feature in your case because it goes back to the issue of the nature of that wish and how that plays out or was it really that there was potential great benefit for understanding the disease and the research and there was minimal risk?
MS. FLYNN: It s hard for me to put a value on one or the other. It certainly, in this case, would be a combination but were she never to have expressed a particular view about the research or just to never had that conversation. My view is that so much of what s necessary here is not really of great risk and in fact, we know that there are lots of folks who are more than willing to accept these risks that we re putting in so much protection here, we re not going to get a lot of research and it s basic science. It s not going to offer a direct benefit. It s not highly risky and we have lots of people now who are indicating a willingness to participate in it but now it seems to me that we are suddenly seeing it as an area of potential real concern and requires this special elevation to a separate panel. I don t understand the need for that.
DR. SHAPIRO: Thank you. I have Jim, Bernie, Alta and I have some suggestions here also.
DR. CHILDRESS: I d like to speak in favor of the proposal that Alta made with Alex's elaboration. I think it s the direction to go. It keeps some of our, and Steve s, now I m speaking specifically of how to handle what here, here s the no, but be studied in obviously a more positive way. I think this does have the advantage of keeping a particular concept of consent that would work with them on the other side, very, very clear, protecting it, but keeping also, certain values simple to our whole discussion and assessment of protocols while allowing some very important research to go forward. And I think the kinds of directions that have been proposed in building on Alta s statement, would permit us to do that and I appreciate the concerns that Laurie s expressed but I think that given the kinds of modifications that have been proposed and what the panel would do and given the experience, I didn t serve as long on the RAC as Alex did, but my experience was very consistent with his. I think we re sort of overstating the barrier. Yes, there is a hurdle to be jumped over but that doesn t mean that it s going to be set so high that it would create problems for very important research to go forward.
DR. LO: I guess I still have concerns about the OPRR or Secretary of HHS alternative. I think that the RAC was a very special set of circumstances. We re talking about type of research that was new, unprecedented, and a lot of concerns about the unknown. A lot of symbolic concerns, a lot of concerns about long-term unanticipated side effects. Relatively few proposals, at least in the early stages to my understanding, were being proposed because the science wasn t really there. And, you know, I think, my hat has always been off to those of you who have served on the RAC and really did a lot to sort of clarify the issues and establish a standard of care and really, as Alex, pointed out, strengthened a lot of the protocols in terms of making them better science and better ethics. I think, I m talking about, I think, a different set of issues here. We re talking about interventions that are commonly used in clinical practice where there isn t a whole lot more of anticipate. I try to ask a lot of our neuroradiologists, what s the data on the risk of PET scans and MRI scans in terms of anxiety, long-term headaches? Is it more or less, are these side effects more or less prevalent in people with various conditions? We don t know. We have a lot of opinion. But, these are things that are done a lot and radiologists have standard safeguards. I think that, you know, I come from the West Coast, to come to Washington for a meeting—if I had a graduate student fellow who wanted to do a project, no matter how good the science, that project would not get done if we had to come to Washington to come to a meeting. I agree with the idea, what Eric said, that we need standards, a common understanding. We need a registry. We need to develop a sense of what really ought to be approved most of the time and what's really very different. But I just think that to have a committee that meets in Washington, that's hard to get to, and you have to schedule it in advance does present problems when you have a high volume of protocols that want to come before it.
One of the things I like very much about 12(a) is where we talk about a ratio of benefit to risk, the project is of exceptional importance. We're starting, it seems to me, to sort of get a sense that of all of the studies out there that are greater than minimal risk, there are some that we feel differently about than others. Alta keeps talking about we're close to the line. If we can try and define what those are, that's fine. I'm a little concerned, frankly, that we're going to end up calling things minimal risk that I'm not sure are minimal risk. Does any degree of radiation take you out of the minimal risk category? Those are the kinds of questions we want to get to.
But there are a lot of IRBs and people who say that's different than everyday experience, even if the absolute numbers are the same, that qualitative nature of the risk is different. So I think we're taking a concept that is based on everyday experience, which is amorphous and then we're trying to use it as a sort of branch point for regulatory provisions. I'm just afraid we're going to end up with some decisions and a whole class of cases that just sort of goes against intuition. So 12 I have real concerns about.
I like the idea of bringing together a panel to sort of take the data that's known, look at the protocols, obviously, look, here's a group that we think really IRBs should be able to approve, and here's a group that we'd be very disturbed if they approved that a lot. 12(a), it seems to me, gives some local flexibility. I'd like to hear more discussion as to whether (a) people think this would be effective, that is the local IRBs plus sunshine, and (b) given that we now have not just recommended but urged in regulation there be two IRB members who represent persons and families with a mental disorder, whether that change in the IRB goes some way towards addressing some of the issues that 12(a) is meant to address.
I actually have some concerns about the publicity. When you have sunshine, there's both good publicity and bad publicity. Are we going to get more thoughtful discussion, or are we going to get more sort of newsworthy drama? And I'm not sure.
DR. SHAPIRO: Let me just interrupt here because I find an unusual situation. I have my own perspective on this that may be somewhat different than at least the combinations I'm hearing here. I'd like to just be talked out of where my head was on this because probably I just haven't seen this carefully enough.
First of all, if I look down this tree, which I find extremely helpful, I'm not as worried as Steve, I'll use your name but it means for your group, I don't mean to attach this to you, I'm not as worried when I get to the prospective consent to protocol as keeping, as it was put, the kind of integrity of the idea of consent. We're already down a branch where consent is not possible. We're dealing with people incapable of giving consent. And that's why I had thought that, as 11 indicated, and as you indicated somewhat actually in your own kind of musing about this, that there might be some possibility here to talk about types of research or classes of research that one could have some prospective consent, although we might want to invent some other word other than consent, because that would allow more cases to go down to the "Yes, LAR monitor."
So it's not like you just do it and that's the end of it. You have a legally authorized representative monitoring in the best interests, as we say down here, et cetera, et cetera. So it seems to me, my own view is that there at least is some argument that we ought to allow more cases down to that "Yes, LAR monitor." That's just my own view.
With respect to 12, 12(a), et cetera, et cetera, that is 12 being the Secretary's panel, and I accept the notion that that has to be fleshed out in some way that's more effective, but the idea of whether public disclosure is a good or a bad idea, whether that allows for too much IRB flexibility, that is, is that a huge loophole which some army of people are sort of going to march through in a way that overwhelms the system. I have I think a rather different view than has been expressed around the table about that; namely, I believe that public disclosure and public disclosure to sponsor would be very effective. I know I'm just asserting that and I certainly can't provide you with a detail. But that means that not only the local IRB has put itself on the line publicly, but so have the sponsors who if they fail to object. And that's a pretty major influence for a lot of the research, especially the research that may be financed by the Federal Government and so on.
So it seems to me that while in this period where we're trying now to struggle with these recommendations and develop some guidelines, this is not something that's going to be put in concrete and stay that way forever, it will evolve on its own as we gain experience, that there really was some benefit to allowing some local IRBs some flexibility in cases that they found compelling. I chose the word compelling in that thing because that meant a lot to me. I understand everybody has a different view of what compelling means, but I meant that this was something which they believed to be important. And if they decide to go ahead, if anybody objects, they've got to be able to explain that compelling to somebody at some stage.
I thought if you took some combination, I understand it's not well articulated here, what is 12 fleshed out and 12(a), allowing IRBs to perhaps choose, as I said before, amongst these paths that you could either describe this as allowing more thoughtful flexibility or as allowing a huge loophole through which some people are marching inappropriately; that is, doing things which we would all think inappropriate.
Now all of that says that you believe that with the guidance we've provided that the IRBs at the local level will be doing their job well. I understand that. It puts some faith there and time will tell, if we ever recommended that, time would tell whether that faith was justified or unjustified.
Given that, if these recommendations go forward, whatever we choose in this area, we will have substantial new guidelines in place for IRBs to deal with in this area. It's not like it depends only on any one of these recommendations. And that that made some sense.
So I have two concerns. One of which is I think we share, that is we want this "No" to be not just no, but some process which is believable, and I believe in some flexibility in that process and I'd like to provide some flexibility and experimentation in that process. And I also believe we want more, I would allow more to go under the "Yes, LAR monitor" than I think seems to be the general feeling. It seems to me to not allow that means, and I understand this is an open issue, it really depends on how much you think you can rely on the IRBs to do their work. That's what it comes down to in my view. And I understand that we don't have an answer to that.
Alex?
PROF. CAPRON: I guess I would ask you, you say you have no evidence, and you almost started to say you have no detailed evidence and you realized you have no evidence, it's supposition. But on the other hand, given the recent studies of IRBs, given OPRR's report on UCLA's IRB, OPRR's report on Maryland, two of the most distinguished psychiatric institutions in the Nation, what basis would we have for thinking that giving the IRB more discretion is going to lead to more defensible results?
DR. SHAPIRO: That comes down, the way I think about it, to whether we think this public disclosure or LAR monitoring means anything or not. Maybe I'm wrong, but it seemed to me that those were meaningful things. If they're not, then, of course, it's an empty gesture.
PROF. CAPRON: I think the LAR monitoring is a useful adjunct if you're dealing with a situation in which the person has consented previously and you still want to make sure someone who is competent is watching out for their interests, or in which you have a prospect of benefit and again you want to be able to get the person enrolled.
DR. SHAPIRO: The prospect of benefit doesn't—I agree with that.
Either of those uses of the LAR I'm comfortable with. But the IRB, in many cities an IRB could run in the local newspaper or something a little announcement that it has approved a final protocol. Why would that generate a great deal of attention from anybody?
DR. SHAPIRO: My own view is if both the sponsor and the public know that interested parties will, if they're interested, take advantage of the information that's available. That's just my own.
Arturo, you've been waiting a long time, then Eric, then Alta.
DR. BRITO: What I have to say goes along with what you just said. What would be wrong, going back to what Laurie's concern is, going down to the "No LAR" on the right, why can't that divide up in two arms? There may be, I'm sure there are plenty of situations where there may be no prospective benefit, there was no prospective consent, but the LAR may go ahead and approve and might have justification for approving; for instance, your daughter giving previous approval or wishes to be involved in something like this. So we're trusting the LAR to be protecting that individual. We've already come to that conclusion in those situations, right? So why can't we trust LAR to say, okay, even though this study is greater than minimal risk—that's another point I was going to make before, I still think that's very subjective, going along with something Bernie was saying—but greater than minimal risk because they're going to get an MRI, but I feel it is worth taking this risk because my daughter previously told me that she would want to be involved in this study. I just think that if there is justification for LAR, we should honor that. I just think there's other possibilities here, going along with what you just said.
Going back to what Alta said a while back, I think a big part of this problem is the quantification or standardization of what minimal risk really is. I still believe though that we need to keep the two-tiered system greater than minimal risk and minimal risk, because I feel that it's always going to be very difficult to quantify things in that sense. But I think that we also need to make it very clear that there need to be standards in research. For instance, what I'm hearing in MRI, when I heard Tom say that and I asked some people from NAMI during the lunch break about this, why isn't MRI considered more than minimal risk or greater than minimal risk in someone with mental illness? What scientific proof is there of that? And I think that's the problem, there's a lot of subjectivity with IRBs individually determining what is minimal risk and what is not. I don't think it's a problem with the number of tiers, I just think it has to do with specific tests.
DR. SHAPIRO: Eric, and then Alta.
DR. CASSELL: I changed the recommendation to 12 somewhat to say "protocols involving greater than minimal risk but no benefit to the subject, where an LAR monitor exists should be reviewed by a local IRB. If the benefit in terms of knowledge is sufficient to balance the risk, the IRB should approve the protocol so that it might move to a special panel of OPRR for final approval."
So let the IRB deal with the weight of it, get all the simple issues resolved, and then if that's what it is, then let it move on to this special panel and get a final approval there. I also don't think that the public light in this sense does anything.
DR. SHAPIRO: Okay. Alta.
PROF. CHARO: I'd like to address a couple of things that came up particularly in Laurie and Harold's comments. I think that the governing ethic with which we approach research in the United States is not one of a kind of communal benefit and communal obligation. We could develop that. We could say as a matter of intergenerational justice, I benefitted from research on other people, therefore I should be drafted into research and it will benefit the next generation. But that's not the way we've chosen to go, although I think it's entirely defensible in some ways to make that argument. We go for a very individualistic look and we say are people willing to volunteer individually.
Now, one of the things that has frustrated me is in trying to divine the individual preferences of people who can't speak for themselves. And Laurie, you asserted at one point that most of these people would like to be in this kind of research, referring to research that has no benefit to them and which has risk levels that are just above to someone's specified level above minimal risk, right? Research that poses some degree of risk. And my question is, how do we know this? You've got anecdotes, I've got anecdotes. The only thing we really know for sure is that most people don't volunteer for research, and of those who do, extremely few volunteer for research that has no personal benefit.
So I'd like, number one, to suggest that the recommendations ought to include an effort to actually find out what people do really want. Because consent is not an end, it's a means to an end. Consent is a way to find out what people want and facilitate their choice. If we can find out what they want and facilitate the choice in a way that doesn't involve traditional informed consent, we do that. And that would mean trying to understand, and I would challenge some of the people in the mental health community to work on this kind of research, trying to understand what people say they would be willing to volunteer for and then double-checking and finding out how much they actually volunteer for. Because we all I think believe ourselves to be more altruistic than we actually are when push comes to shove. But you're quite right, this is a special population. There might be analogies—people with breast cancer who say I'd volunteer for this kind of non-beneficial research and how many actually do—to get a handle on understanding what's going on out there.
If somebody could persuasively argue that the overwhelming majority of people who can't consent for themselves in fact want to be enrolled in non-beneficial research of some magnitude of risk, I think all these recommendations should be revisited. But I think until we can get that kind of information, you have to presume that these people are no different than anybody else, which is that a minority of them are actually willing to offer themselves up as altruistic lambs and we have to try to facilitate their choice of non-volunteerism.
Which is why I'm very comfortable with the way we've gone so far. I'm moveable on this question about blank check versus narrow consent. But on the bottom line of whether or not they should be enrolled without consent and why that matters, I think that you can't evade the kind of fundamental individualism here of facilitating people's own choices. We're not allowed to just say that it is compelling research and, therefore, we're going to draft you into it no matter how many people vote in favor of it.
Finally, and very briefly because I know I've spoken too long, on the 12 and 12(a) thing. I think 12 can be made into something that's highly efficient and does not require a trip to Washington. Once categories have been announced, IRBs are able to approve the protocols right there locally. They don't have to send somebody to Washington. On 12(a) with sunshine, not only does it bother me in terms of implementation, but I think that, again as a matter of individual rights, no matter how many people agree politically out there in the sunshine that it's okay to draft me into research that you find compelling, I find as a matter of principle that it's wrong for you to be allowed to draft me because they all think it's a great idea. And so it's a matter of principle as well as pragmatics that makes me uncomfortable with that particular recommendation.
DR. SHAPIRO: Diane.
DR. SCOTT-JONES: I think the comment about our definition of minimal risk, it seems that a lot of the discussion has centered on what procedures belong in the category of minimal risk and what procedures then belong in the category of greater than minimal risk. I think there are other ways of looking at how to label particular studies minimal risk or greater than minimal risk. I think we have a very good discussion of that on page 132, which actually comes under Recommendation 5, where we talk about the importance of looking at the risk categories in context and that a given procedure may not necessarily be risky for all persons in all ways of administering that procedure. So there's very good discussion here of how say a venipuncture might be disturbing to some people who have limited understanding of what is being done to them when they undergo that procedure.
I don't know how we can write it into our specific recommendations here, but some way we ought to get away from the idea that we can create a listing of procedures and call those minimal risk and another listing and call those greater than minimal risk, because over time those procedures will very likely change and new ones will come into existence. So I very strongly favor something that is more contextual, which will require that IRBs and investigators use good judgment and good rationale for whether they have a minimal risk study or a greater than minimal risk. I really think we should get away from the idea of cataloguing procedures as one or the other.
DR. SHAPIRO: The area where we are having great difficulty right now is the greater than minimal risk/no prospective benefit. I haven't heard so far at least, maybe that will come up, any compelling argument that something like writing recommendations around this tree, taking advantage of other comments that have been made here, would present us any insurmountable difficulty except in the area called "No" here, the final no here, which I think we all agree shouldn't be left like that. The question is, what set of procedures would we allow to take place once you're in that "No" category?
We have the recommendation, which can be fleshed out in response to some of the interesting ideas here, of making something workable out of what we loosely call the Secretary's Panel. Maybe the first step would be to stop calling it the Secretary's Panel because that sounds by itself so ominous that it's not likely, in my view, that we're going to get it. But maybe we can think of some procedure which is national in scope and yet is not at a level where it just will never be used, because I don't think anyone has expressed that prospective. In addition, that that will also be the source of guidance as we go along as to how IRBs should behave. So it's a kind of two-way street is what I understand people to favor here. But I haven't heard anything else. I don't see much support, for understandable reasons, for anything else right now.
Bernie?
DR. LO: It would help me if we distinguished a lot of ideas that have been combined here. I heard some people say that the IRB should have some discretion and then other things might happen. So one proposal was someone ought to require an additional layer of review on top of that IRB, some sort of panel that would be empowered to look on a case-by-case basis at these other protocols that the local IRB approved. The second proposal was that a panel be convened to try and draw broad categories of guidance for local IRBs to apply. The implication being that if we could set some standards here, IRBs would be on surer ground and we wouldn't have to provide as much extra scrutiny of individual protocols. And then there was an idea which is somehow getting a handle on the combined experience of IRBs. Eric talked of a registry. Harold talked about a public disclosure of protocols the IRB was approving. The idea I think would be that somebody could then go back and say let's look at all the proposals of this ilk that the IRBs around the country have approved in the last year and analyze them and see whether it makes sense, whether there are patterns emerging, where there are danger spots that no one was aware of.
It seems to me those can all be separated out. I'd like to maybe encourage us to think of each of those separately.
DR. SHAPIRO: Bernie, I think that's helpful because I think you're quite correct to say that all three of those ideas have been around and suggested here. But what would you think, if we were to flesh out a recommendation like this, and I don't have the words right now, for really a single panel of some kind doing all three of those things, because that's where the information will be coming to, that's where the discussions will be taking place, that's where the case-by-case evaluations will be taking place, and you'll build up some knowledge over time. The idea being that this is not just a panel that says yes and no, but it's a panel that actually develops ideas which are helpful to local IRBs and would have as its charge that it really should do this because it wants to shed itself of some of these responsibilities over time if evidence and experience indicates that that's appropriate.
But I think the three ideas you have are all genuine and all important.
DR. LO: In some sense, the RAC did that, right?
DR. SHAPIRO: Yes.
DR. LO: The RAC both reviewed individual protocols and then developed some general guidance.
DR. SHAPIRO: Correct.
DR. LO: I guess my concern is the pace at which centralized "blue ribbon" committees work. This is going to be a committee that people are going to do on top of everything else. It's going to take a long time to develop these general guidelines. I'd like in the meanwhile while that's being done to have some process that provides some balance between gathering information on what's really going on out there but allowing things to proceed at a reasonably good pace. I just am a little skeptical that one central committee is going to be looking at all of the protocols from around the country that fit into this "No" block. That's a lot of protocols.
PROF. CAPRON: Don't generalize on the pace issue from the experience of this Commission.
DR. CASSELL: I think that's why the local IRB should see it first so that it screens it out and you don't have everything going up there. You have the local IRB handling the first look.
DR. MIIKE: Bernie, it can be a live process where you have some central body set up some interim guidelines by which IRBs then begin to work. Meanwhile, that central body does all the other things and revises the recommendations.
DR. LO: Then I'd like having some sort of first-cut at guidelines going to IRBs, saying this is what we'd like you to work with, for the next six months we're going to monitor you, we want you to come back and tell us what the problems are, what works, what doesn't, we're going to review everything you approved or some sample. That makes more sense to me. Someone would have to work out the numbers of protocols that would be coming—
DR. MIIKE: Remember, I came into this with Laurie saying we should have approval by an LAR whether or not there was benefit or not even on greater than minimal risk I have been persuaded that we need to distinguish between the two sides. I think that if much of that decision can be held at the IRB level, it is just another thing for the IRB to consider rather than another step aside. So that an investigator brings a protocol in and says, "By the way, we have subjects here that were not able to give permission and it's greater than minimal risk," and it slots that into another category in which the IRB can make a decision. But they can make that decision all at the same time.
DR. SHAPIRO: Further comments?
PROF. CAPRON: Is this a matter on which, as your message to us in advance said, if there aren't three or four people who really favor 12(a) that you will simply note a concurring or a dissenting opinion at this point?
DR. SHAPIRO: Well, I don't know if we're at that point yet because we need to flesh out some of these things into actual language. But I think this may be an issue on which there is sufficient disagreement amongst us so that those who feel strongly, whatever position the majority of the Commission adopts, others may feel strongly enough to say something about it, in which case they are certainly welcome to do so. And as I said in my e-mail to you, while I think the primary benefit of arguing all these things out is so that we all get a little smarter, but the primary objective is not so that we all agree to everything. There may be alternative points of view which are worth surfacing, and that's a benefit also. But I think trying to talk ourselves to consensus has the value of testing our own ideas and seeing whether we do find some genuine consensus but I don't want to hide disagreements beyond some superficial consensus.
Laurie?
MS. FLYNN: Given the choices we have, I certainly like a lot about what's in 12(a). I believe we need to engage the IRBs in an ongoing process where they grapple with these issues, where they learn these issues, and where we enable them to come to understand much more than some of them may what the compelling needs may be and that some of these studies are really not of great risk.
I also think that it's important to recognize that even though we have tended here, and it is continuously reinforced I think within our process, we tend naturally to hear, as we should, about cases that are of alleged abuse—we have heard about a variety of individual stories, we are aware that there is a need for some reform and some additional safeguards—but we also need to recognize that the vast majority of the folks out there in the IRB system and the vast majority of folks out there in research are doing a good job, are wanting to do a stronger job.
I think with the work that we've done here and the visibility that our discussions have had, I think that if there was ever a time to really follow in on their interests, continue to work with them around how to better understand the necessity of these protocols, this process has set the stage. So I think that it's particularly useful for us to move in the direction of the flexibility that's outlined in 12(a) and remaining with the fundamental structure of our system, especially given the other kinds of supports that we're recommending be put into regulation.
DR. SHAPIRO: Trish, excuse me.
MS. BACKLAR: I'm going to be going very soon, so that's why I just wanted to say a few words about this. I think, Laurie, one of the reasons that we talk about the bad cases is, of course, the bad cases count when people are harmed. As Alex has said, when we look through protocols, one protocol that harms people is enough.
But I just want to say a few words about the Recommendation 12. I actually really agree with Alta. I'm very concerned about the public comment part. I can't give you a process of doing this, but I see it as a process that would work backwards and forwards between a review committee and the IRBs, a kind of secretary that would review these in such a way as to develop a template for IRBs, a guidance for IRBs.
But the public comment I think really won't work. I'm thinking of a class that I'm teaching right now in bioethics and telling them about the waiver for research with stroke and how our university in Portland had put advertisements in the newspaper. Nobody had ever seen them. And then when I showed them the advertisements, they didn't understand them. It sort of misled them about what was going on. And I think the IRBs in our city at least have had not very good feedback when they have tried to get public comment.
DR. SHAPIRO: Let me say a word about where I think we are and what we should do next in order to move this process forward towards completion. Let me make an observation, however, on this issue of who reads the newspaper. There are, of course, lots of things like this, including the fact that most surveys haven't the slightest idea. They know there's a government crisis, they don't know if it's in a surplus or a deficit or which is the problem, they can talk about it for ten years in the newspaper every night and people don't know. But people who are interested and care about it do know and they tend to move the system. And so even though there might be 98 percent of the people or 99 percent who don't have any concept it was ever revealed, I think there's still some benefit. But I don't want to press it on because I understand we will disagree on this.
I think that where we are right now is that we ought to provide to the Commission within the next week or so a revised set of recommendations that go from 8 through what is now, I think, 13 that will build around this tree but it will flesh out a good deal with the so-called "No" lower right-hand corner along the lines that have been suggested here today. And we'll see how the Commissioners feel about that once we flesh it out and put language beside it.
As we go through this, we will also consider whether there are some alternatives to consider, which we'll share with you at that time, trying to take as much advantage of both the comments that have been made today. Because I think there remain some concerns and some disagreements amongst us that may be unresolvable, and that's fine. Then we'll have some different opinions reflected in the report. I think we'll try within the next week or so to get a couple of alternatives in front of you and just see how we feel about it and decide finally how a majority feels in our next meeting, and then we'll just go ahead with that.
I think we have talked this out long enough. We have to face the fact that there are allegations on all sides on every issue. There are allegations that there are too many people that are not treated well. There are allegations it will stop research. There are allegations here, allegations there. It's very hard when you come down to it to get any information on any of the allegations on any side of the issue. And so we are faced with a lack of real data, what normally might try to guide us. So we have to have some process which develops that more effectively over time and, as Trish said, have some flexibility in the system.
But I think that we've talked about these long enough today. I think we know where we all stand. We all ought to be thinking about it. And I ask you once again, if you have thoughts that you can articulate in written form and share, that would help us as we try to develop this over the next week or so. We don't have to finish it but we have to get these alternatives in front of you within about a week or so. We'll do this by e-mail or some other form. And then we'll just see how we respond to that. Because it seems to me we've said enough on this today, but I don't want to close off further discussion. I know we're about to lose members who have got planes to make and so on.
Laurie?
MS. FLYNN: I just have one related point that I think was mentioned and I do think it's important. We're making some assumptions in the absence of data about the willingness or lack of willingness of individuals with decisional impairments to participate in research that may be of greater than minimal risk that does not offer them direct benefit. We've highlighted that as a problem and we really don't know what the willingness is of that subject population to accept those risks.
As we heard our board member here from our organization this morning talk about, one of the things we've tried to do and that I think I can flesh out and share over the next week is we've tried to go out via an admittedly not representative but nonetheless useful e-mail survey to a variety of our members around the country, and we have a very large membership of people, 85 percent of the membership who have these significant disorders, to ask them (a) have they ever done such, have they ever participated in such studies; and (b) would they be interested or willing to. I think our preliminary results indicate that a lot more than you may think people with these disorders recognize the value of participating even though there's no direct benefit. And it might be useful to try to raise some discussion with the subject population about these issues to begin to bring some data to the discussions over time.
DR. SHAPIRO: I'm sure that would be and I'd very much like to share that information. This is difficult information and evidence to gather, as you appreciate as well as anybody else. But everything is building towards a better understanding.
Diane?
DR. SCOTT-JONES: I have three comments that I would like to make before we break today. One has to do with the regulations regarding children. There have been references to children in speakers from the public today. My understanding was that in this report we are not addressing the issue of children's participation in research because that's covered under separate regulations and those regulations are somewhat different, especially when it comes to how you categorize risk. And I think we say that in a footnote in the very first chapter. So I just want to be clear that that is the case.
DR. SHAPIRO: That's an issue some of us have been discussing today, and if there's a footnote, I don't have it. But the intention is, you're right, this is really intended for adults. But I think we need some language which would at least recommend these ideas to those concerned with regulations for children they may wish to consider.
DR. SCOTT-JONES: We have a footnote on page 1 of the first chapter as footnote 1 where we mention the Federal regs that apply to vulnerable populations. So we do have that and there are other places throughout the report where we do talk about children.
But I have a couple of other—
PROF. CAPRON: Could I respond directly to your point and then yield the floor back to you? I would suggest that on page 117, on lines 4 and 5 we have the following statement: "In this concluding chapter we summarize our recommendations and identify the individuals or groups to implement the recommendations." I would suggest either the next two sentences or a footnote at the following two sentences, "Our conclusions and recommendations directly address research that may involve adult patients as subjects in research. Those charged with reviewing and implementing our recommendations should consider whether any need to be modified when applied to research with children."
We cannot go through, Alta convinced me of this during a break, we cannot go through now and fine tune each of these. But if we alert there that we were thinking primarily of adults when we were writing this, that I think is the point to drop that footnote or add those two sentences to the text, whichever, and I will give the staff that language.
DR. SHAPIRO: Laurie?
MS. FLYNN: I understand that we are focusing on adults. But what I heard from these mothers was their youngsters are now not capable, they're not likely to ever be capable. The role that these families are playing in making decisions, which is a role based on trust in their caring about the welfare and benefit of their youngster, they will have that same relationship when that youngster becomes 19 or 21 or whatever. They will be standing in that same place. They will have done those same things. But according to the way we're drafting this, they will suddenly have a lot less to do and be trusted a lot less for kinds of research.
DR. SHAPIRO: That's an important point.
I want Diane to get to her other comments.
DR. SCOTT-JONES: Okay. I have two more points that I want to make. But in response to what Laurie said, I agree with what Laurie just said, but there's also the issue that we've been accused pretty directly of stigmatizing the persons who are the subject of this report. I think to assume that they will be in some sense children, even though in some ways they will, I think that's demeaning to them more so than we've been in this report.
But my second two points, one has to do with my also listening to the people who spoke to us from the public today. I was really struck by the possibility that when people are thinking about participation in research, they are not really governed by the two concepts that form our analytical frame, and those are risk and benefit, it seems to me that there's at least one other element, and that's the notion of hope for people who have been perhaps made to feel hopeless at times about the plight of the persons in their families. I don't think that people are actually making decisions on the basis of risk and personal benefit. There is this idea of hope, even if the hope extends a generation away. I don't know how we can incorporate that into our report at this point, but I believe that our analytical frame may not represent the frames of mind of persons who are caring for people with mental illness.
And then my final comment is that I'm very concerned about the strategy that we have for putting the report together. I know that we don't have time to go through in detail, but one of my concerns is that reading through chapter 5 and getting the gist of the recommendations and, more importantly, being able to see them as a set of recommendations is made extraordinarily difficult by all of the explanations. I believe it would help to see these recommendations as a set if somehow this chapter could be organized differently without so much coming between one recommendation and the next and without the extensive introduction at the beginning which really repeats. I think it's very important for this report to be as concise and crisp as possible. I just hope that we can work toward that.
DR. SHAPIRO: Those are very good points. As you know from what I told you before, any specific recommendations we'd be glad to look at. We need all the help we can get. So please let us know.
Alex?
PROF. CAPRON; You said we're going to be looking at 8 to 13 again. I wanted before leaving to offer the following language for 8 and 10, it doesn't seem to me they have to differ, and I will leave it with you but I'll read it out.
Recommendation 8. "An IRB may approve protocols in this category of research with subjects who are capable of making a decision about participation provided that informed consent to participate will be obtained before a potential subject is enrolled in the study." Isn't that a straightforward way?
And it seems to me it applies for 10, which is the other category of research but the same thing as if you have a capable. I'll leave you that language.
DR. SHAPIRO: Okay. Yes, Steve?
MR. HOLTZMAN: While we just have the people still here, a sense of the Commission. I feel like we've gotten ourselves in a box. What I mean by that is, at least I'll speak for myself and test it on others, when I look at the protocols which spur me to want to erect the protections, particularly down in the right-hand corner, and then I look at the protocols about which people are concerned that we're throwing the baby out with the bath water, there's no overlap in those protocols whatsoever. So if others share that sense, how do we get ourselves in that position?
PROF. CAPRON: Well, I don't think that's true.
DR. SHAPIRO: And I don't share that sense.
MR. HOLTZMAN: You don't? So that when one looks at the kinds of protocols where people are saying I'm very concerned that a PET scan will be defined as more than minimal risk even though, that's going to be—
DR. SHAPIRO: The issue to me is not whether something is more than minimal risk or not. The question is what's the appropriate level of protections for any particular protocol. And we're just saying that once it goes over minimal risk, there are certain things that are required. Other things may be put in, but certain things are required.
Now we tend to get in the cases before us extreme examples. So, yes, they are far apart. But I think the problems don't go away, the fact that there's a spectrum of issues to deal with and there's a spectrum of protections to deal with. And what this says is if it's greater than minimal risk, there are certain requirements; they aren't all the requirements, they're just some of them, but these are required for everything above minimal risk. But within the greater than minimal risk categories there are all kinds of protocols, some with much more risk than others, and you wouldn't want to see the same protections in every single one of them. That's what an IRB is for and that's what investigators are for is to understand just yes, there are certain requirements that come in that they get by getting greater than minimal risk, but then there's a huge category of research in here and the local IRBs have to decide what set of protections to wield in this case.
But I do think there's a problem with this and we're going to have two alternatives in front of us, I hope, by the time next week rolls around, one of which some of us I think will consider as being too lenient and others won't. And we're going to have to decide just which way we want to go. And in my mind, it really is a question of how many protocols are you going to get down the right-hand side of this page, not only the lower right, but the upper right part of this page. I think there are good arguments on various sides here, but we're just going to have to decide which are the most convincing.
When we send out these to you, please, some of you are very active participants in this e-mail and others are not. If you really want to have an impact on what our choices are going to be at our next meeting, we have to hear from you because we really want to be responsive and I want to put something in front of you that is fair and reflects your perspectives on things, although in this area we have different perspectives and there's likely to be at least two proposals.
DR. BRITO: Since we spent so much time on the bottom right-hand corner, can we go back up to line 7 for a clarification? Maybe Steve or somebody else in that group. When we put LAR monitor under the "Yes" on the top right there, how does that differ from "LAR approves." This means it's just the LAR understands the fact and just makes sure everything is going along okay and there's no other procedure?
MR. HOLTZMAN: It was meant to reflect what's in 11(c), I believe.
DR. CHILDRESS: Continuing or withdrawing would be the key—
DR. SHAPIRO: Yes, that's what it is.
DR. BRITO: Okay. My question becomes then, going back to the prospective consent to I guess we're talking about a specific protocol, I'm not sure we came to agreement on that, but a specific protocol, what happens if the protocol changes but doesn't change where you increase the risk anymore than it started? For instance, there's some modification or something, does it still go to the "No" and therefore you pose a question for prospective benefit, or does it go to the "Yes?"
DR. SHAPIRO: I understood, although Steve had some ambivalence on this, I think it's fair to say, I think most members of the Committee said they thought of that as parallel to the informed consent and then you dealt with a particular protocol. I'm not trying to defend that, I'm just trying to describe it.
MR. HOLTZMAN: Okay. And so if you change the protocol, there would be a new consent involved.
DR. BRITO: There may be a point here where you don't have to get to the question of prospective benefit. If the protocol changes, just some minor modifications where the modifications are all at minimal risk, then maybe this is one of the exceptions where you don't need to go and ask the question about prospective benefit.
DR. SHAPIRO: That's an interesting idea. This is all greater than minimal risk. What you're saying is if you look at the changes in the protocol and they're all minimal risk changes, that is as added or subtracted or something are all sort of minimal risk procedures, wouldn't that be adequate?
DR. BRITO: And that might minimize how many things go down to the bottom right-hand corner.
MR. HOLTZMAN: I actually think, and I don't know if we have any data, but the number of prospective consents that are in play compared to the amount of research we're talking about is vanishingly small. So noodling around in this particular area I don't think has a tremendous impact. It has a symbolic impact and maybe a meaningful impact if you think that autonomy is the critical issue and the most important and dominating issue.
DR. SHAPIRO: It's also true that there's a dynamic going on here if new regulations are adopted at some stage that people start behaving differently. But I think we understand these issues. I don't think we can profit more by this afternoon. We all need a little time to sit back and think about it and generate some interest.
We only are a few of us here so I certainly don't want us to take up your time with things that aren't useful or central. My own view is that the recommendations that come here under I guess 14 and 15, which really are recommendations to States, again, I don't want to worry about whether the Common Rule should be amended or we should add a subpart to the Common Rule. We'll deal with that separately. Do any of you have any comments on 14 or 15, or then there's 16 and 17 which deal with professional advice, so to speak, to professional societies, and then 18 and 19 deal with advice or issues NIH might want to consider even though they're called recommendations. I want to come to 20 separately. But are there any issues you want to highlight for us as we think through these issues, at least those of you who are here now? They've received very little of our attention simply because we've been focusing on the more important ones, and I agree these aren't the same level of importance, but there still might be issues you want us to think about.
Bernie?
DR. LO: There was an issue this morning having to do with adequate funding to ensure these provisions. It seems to me that should be—
DR. SHAPIRO: We're going to deal with that.
DR. LO: That should go to NIH and to professional—
DR. SHAPIRO: Yes, those things we are going to deal with. We have to acknowledge that this cannot be done without resources. We're not the resource allocation committee for something but we have to acknowledge it and say we'd expect this, that it's unrealistic to do without supplying resources in some appropriate fashion.
DR. LO: I guess I would suggest that we try to be specific as to who the onus is on. It seems to me it's on funders, it's on institutions for IRB support if we're asking them to take on new tasks, as well as to professional organizations to articulate why this is all necessary.
DR. SHAPIRO: I agree. And I think there is some language somewhere in here that deals with that. But we need to bring it into closer proximity with these and other recommendations. These aren't the only ones, but other ones.
Yes, Bette?
MS. KRAMER: I was just going to say I think it should be a specific recommendation so it takes on more importance.
DR. SHAPIRO: We will. All right, we'll think about that and perhaps have something like that.
Recommendation 20 I just want to highlight for a moment because I think we ought to change it somewhat. It goes back to the issue of an appropriate agency to establish a mandatory IRB registry. At the current time, I'm not sure we've thought that through carefully enough or know what it is that we're registering to really require that. I feel quite uncomfortable with it as it stands. On the other hand, we will be coming out with a report on IRBs later on this year, at least not this calendar year but this academic year, if I could use that phrase, and I'd rather in Recommendation 20 indicate that we're going to have something to say about this issue as we deal with IRBs and something to say about the audit issue and how that ought to be handled rather than a specific recommendation which I think, for one reason or another, we haven't really worked out in our own minds.
So you will see that. We're not going to do anything without checking with the whole Commission. But you'll see something different come out on that particular one.
Bernie?
DR. LO: Can I make one other suggestion? A lot of this sort of research, particularly with drug studies, it seems to me is going to be done outside the purview of IRBs, well, outside the NIH but it may fall under FDA guidelines.
DR. SHAPIRO: That's right.
DR. LO: Should we say something somewhere that, even though for IRBs and investigators for whom this is not all mandated by regulation, we would advise they adopt it voluntarily as sort of good standards of practice?
DR. MESLIN: I think we already say that, but not explicitly. It's in the text.
DR. SHAPIRO: I think that is an important issue because as one thinks of regulations, guidelines, so on and so forth, it is much more complex given the way the research agenda is being distributed around different agencies and so on and private and public than ever has been the case before, which makes it both wonderful in a certain sense and more difficult in another sense. So we do need to acknowledge that, and we'll do so.
All right, my sense is that it would be a good time for us to adjourn unless someone has a burning issue they want to put before us.
Eric?
DR. MESLIN: It's not burning, I just wanted to know whether the Commission was interested in seeing a version of Alta Charo's recommendation regarding a call for more research on the willingness. Laurie has kindly offered to give some anecdotal data, but were you proposing that as a recommendation for us to work out and present back to the Commission?
PROF. CHARO: I was. There's a very first draft that still needs to be tinkered with. It can certainly be put out on e-mail for discussion. I'd like to see that.
DR. SHAPIRO: Why don't we put it up on e-mail and see. When you look at it, think of it not simply as a proposal but whether this is something we actually want to be part of our recommendations. We can get that up pretty quickly.
Thank you all very much. I appreciate it.
[Adjournment.]