Section 77 of Final Report of the Advisory Committee of Human Radiation Experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Recording by Gillian Henry. Final Report of the Advisory Committee on Human Radiation Experiments. Contemporary Projects Chapter 16 Part 3 Deciding to Participate Brief Survey When asked whether specific factors contributed a lot, contributed a little, or did not contribute to their decision to participate in particular research projects, patients typically identified multiple motivations. Most patients reported that they had joined a research project to get better treatment, contributed a lot, 67%, a little, 11%. And because being in research gave them hope, contributed a lot, 61%, a little, 18%. Patients who cited the desire for better treatment as a reason for agreeing to be in research were more likely than other patients to be in a study that they viewed as therapeutic, that related to the patient's medical condition and that involved radiation. In addition to this emphasis on the possibility of better treatment and the bolstering of hope, 135 patients agreed with the statement that they had little choice but to participate and that this belief contributed a lot to their decision. While it is difficult to ascertain precisely what these patients understood this statement to mean, patients elaborated on this motivation in the in-depth interviews, often saying that because of the serious nature of their medical condition and or because other interventions had not been successful, they believed they had little choice but to try research. Patients reporting that they had little choice tended to categorise the projects in which they were subjects as treatment projects compared with diagnostic or epidemiological, tended to report that the projects involved radiation, that they did not feel they had enough information and that the research was related to their medical condition. Altruistic reasons also played a part in many patients' decisions to participate in research. Specifically, most patients reported that they looked at participation as a way to help others, contributed a lot 76%, a little 18% and as a way to advance science, contributed a lot 72%, a little 21%. Patients also frequently said that they had joined research projects because it seemed like a good idea, contributed a lot 48%, a little 17%. The project sounded interesting, contributed a lot 53%, a little 24% and they had no reason not to participate in medical research, contributed a lot 56%, a little 15%. In-depth interview. In reporting how they had decided to participate in research, in-depth interview patients described many different processes, ranging from the very deliberate weighing of risks and benefits to the quicker decision of just taking action. Doctors, for example, my doctor, the doctor, a particular doctor or referring physician, were frequently identified as the key agent in the respondents' decision to participate in research. Patients expressed a broad range of reasons they decided to participate in biomedical research. As in the brief survey, for people in therapeutic research, the primary reason for participating in research was to obtain benefits, either through an experimental treatment they hoped would be better than standard treatment or through the closer medical attention they believed they would receive through research. One woman reported that she was participating in a treatment trial, specifically to obtain an experimental drug that she believed looked promising. Furthermore, she wanted to receive it in a controlled environment where she could receive good follow-up and where researchers would document the drug's effects. Another respondent commented that since doctors at the military hospital where he received his care were very busy, he could receive closer attention and obtain appointments more easily by enrolling in research. Some patients who reported being in therapeutic research hoped that the research would give them more time. All I wanted at that point was five years to get my boys through high school. I want longevity. I don't see myself wanting to just pass away. Some patients decided to be in research because they believed that newer therapies might inherently be better. If there's something new on the market that might be better than the traditional program they've been using, why not try it? Mirroring the brief survey finding that 31% of patients felt they had little choice in joining a research project, many in-depth interview patients who participated in therapeutic research remarked that they had joined because they believed they had no choice, meaning they had no medical alternatives. My doctor told me if I do not take the drug in a couple of months I will die. So I had no choice. Who wants to die? Nobody. Another respondent said, I had one more option as he, note the doctor and note, put it. Hope and desperation pervaded the remarks of many terminally ill patients. Patients said they wanted to try anything or that this was their last resort. One man explained, well what was driving me to say yes was the hope that this drug would work. When you reached that stage and somebody offered that something that could probably save you, you sort of make a grab of it and that's what I did. This same patient noted that he had first declined what he had considered a very aggressive therapy because at that point everything was pretty okay and there was no need for me to do any wild things. Later when his condition worsened he decided to participate in the research. One of the most influential forces in patients decisions to enrol was doctor's recommendations. One patient described the process of her enrolment. He, the doctor, asked me if I wanted to go on it and I said, if it's what you think I should do, yes, because you know more about it than I do. He said I think it would be a good idea to try it. Along these lines a theme of trust overwhelmingly emerged. Patients trusted specific physicians, medical professionals more generally, or the overall research enterprise. Trust in specific physicians was straightforward. Basically you know we trust doctor so and so. There was no need to get a second opinion from another doctor. Another respondent exclaimed, oh I love that man. He has kept me alive and I obey him and I do what he tells me to do. Some patients also communicated trust in the medical profession more generally. I have this attitude. They know what they're doing. They wouldn't have you to do this if they didn't know what they were doing and that's my attitude. Finally there were a few patients who expressed trust in the overall enterprise of medical research as well as its oversight. One respondent stated, I do not feel like the drug would be on the market if it were going to harm me and if it would help in any way I'm very willing to participate in this and perhaps other studies. Related were patients who said they decided to participate because of their trust in the institution where the research was being conducted. I think I've got the best treatment down there, note named hospital and note. I don't think I could get any better. Rare were the patients who had less blind trust and considered themselves to be more of a consumer. I sort of take my own treatment in my head and tell them that I'm his client. It's not the other way around. Elaborating on responses to the brief survey, the majority of patients mentioned altruism as a reason to participate. This desire to help others took many forms including helping others who had the same medical condition, advancing medical science more broadly and contributing to society. Most frequently those in therapeutic research seemed to voice a combined motivation of seeking benefit for themselves and hoping to achieve benefit for others. Very representative was the comment I was hoping, if not for me, at least for the next people coming along. For some patients who faced a life-threatening illness, participating in research seemed to offer them a greater sense of personal worth, a chance to contribute something of value to society. One woman said, if I can help find a cure for what seems to be so common, note that is cancer and note, these days I would love to think I was part of finding that cure. For a small number of patients, this notion of helping others went further to be a duty or obligation. I thought well I don't have to do this and then I thought well here I am benefiting from literally thousands and thousands of experiments that have gone before and that are helping to save my life and this one sounded very reasonable to me and it was happy to participate. Similarly one respondent replied, I feel like that, note participating in research and giving blood and note, is a moral obligation as a citizen. You put back into your community opportunities to not only help yourself but other people are real important to me. Only three patients cited monetary reasons for participating in research. Deciding not to participate. It is also clear from the brief survey that not all patients approached to participate in a research project agree to do so. In fact 191, 10% of the 1,882 patients we spoke with told us that at some point they had made a decision not to participate in research. While 112, 59% of these 191 patients had never decided to be in research. The remainder reported that at some time or other they had. 39 were current research participants and 40 were former research participants. Suggesting that some patients discriminate between projects they are willing to participate in and those they are not. Patients who declined to participate in research ranged in age from 21 to 83 with a median age of 56. The patients were of both genders, 53% male, 47% female, predominantly white, 69% with 27% African American and the remainder being of other ethnicities. With wide educational backgrounds ranging from less than eighth grade to those with professional degrees. We asked the 112 patients who had never been in research why when they had been offered the chance they had decided not to participate. The reasons that contributed a lot to their decision were that they wanted to know what treatment they were getting, 64%. They wanted their medical decisions to be made by their doctors and themselves not by researchers, 56%. They believed that being in the medical research project was not the best way for them to get better, 45%. And taking part in the medical research project would have been inconvenient, 43%. Consent and Voluntaryness Brief Survey Overall 83% of patients who told us they were current or former research participants remembered signing a consent form agreeing to take part in research. This was true for 88% of current research participants and 80% of former research participants. Most 90% of the patients who believed that they were current or former participants in research reported that they felt they had enough information to make a good decision about whether to participate. This was the case for 95% of current research participants and 87% of former research participants. Fewer than 2% of current or former research participants felt pressured by others in making a decision to participate. Six patients specifically said that they had been pressured by someone in the medical field, for example, my doctor, the hospital. Four patients reported having been pressured by someone in the military, for example, the military, Admiral on ship. When patient subjects were asked what they thought the policy was for dropping out of the study in which they were participating, 78% thought correctly, according to current research standards, that they could drop out at any time. A variety of other responses were also offered, ranging from not knowing the policy to expressing that it was irrelevant. For example, the entire project consisted of a single survey or blood test. To believing they had to stay in the research project. In-depth interview. On the whole, patients who granted in-depth interviews recounted that the staff involved in conducting research explained research projects, gave participants time to read over the consent forms and confer with family and friends, and responded to participants' questions. One patient said explicitly, it seemed to me that they were well prepared to answer any questions I would ask them. Asked if research staff had provided her with as much information as she needed, one patient replied that they used terminology that I could relate to. They spoke in my language, that was a plus. The consent process in general, and the consent form in particular, held varying degrees of importance for patients. Most patients enrolled in survey or non-invasive projects did not attach a great deal of meaning to the consent form. One respondent, whose experimental procedure consisted of just drawing some blood, thought in fact that his consent form went overboard. For those patients who reported being in research evaluating potential treatments, the value of the consent form varied. For many, the decision to participate seemed to have been made before the consent form was given to them, and they signed it almost as a formality. For a few, signing a consent form symbolised the first step on the path to getting better. Others, however, relied heavily upon the content of the form when deliberating about whether to participate. In addition, several patients noted that they held on to their consent forms, a few even offering them up for the interviewer's review. The notion of trust also accompanied accounts of the consent process. For some participants, the consent form was the means by which patients could authorise trusted health professionals to do what they think is best. One respondent remarked, whatever the doctor was doing, well, that was all right. I consented to this, and let the experts take over then. This authorisation for treatment meant abdicating attention to detail for some patients. I'm the type of person, I don't read all this fine print and all this stuff and so forth. The lady said that we would like to experiment on your body to see what can be done, and it's to help me, and so far so good. While patients attached different levels of personal interest to the consent process, they were clear that the type of information typically conveyed in a consent process is exactly what they would need in order to decide about participating in research in the future. Patients overwhelmingly said that they would participate in a research project again if they had enough information and if the project were explained in sufficient detail by research staff. I'd have to know the what for's, ifs, whys, what they're going to do, or if somebody can't explain what they're going to do to me good enough, I wouldn't do it. Furthermore, several patients stated that they would like to know why a particular study was being conducted and why certain procedures or techniques were necessary. Communication, information and honesty were frequently identified by participants as essential in considering participation in any future research project. For patients who described their own consent process, experiences generally were positive. A few patients reported problems however. Three general problems were identified. One, too much technical information that was difficult to read and understand. Two, an overwhelming amount of information. And three, discussions occurring at stressful or inappropriate moments. A few patients reported that during discussions with physicians or investigators, they relied upon family members to help process the information conveyed. A few patients remarked upon the importance of contact among participants in research projects evaluating treatments. One respondent contrasted the type of information one research participant can provide to another versus that which a doctor can provide. It's always nice to be able to see somebody in the same boat or talk to that person because even though a doctor is very good in explaining things, there are certain things that only somebody who's going through the thing can really know what you're talking about. Consistent with findings from the brief survey in which 98% of patients reported that they were not pressured into participating in research, almost all the patients who gave in-depth interviews believed that the decision about whether to participate in research had been theirs to make and that they had not felt pressured into that decision. Indeed, many patients mentioned that they participated voluntarily. One respondent said, They wanted to know if I would be interested in this. Nobody was pushy, nobody. They just said, here it is. Would you like to be involved in this program? No one interviewed identified pressure from family members. More often, patients remarked that while they conferred with family and friends, the choice was ultimately their own. My family, the people I work with, everybody tells you you have to make up your own mind. Nobody's going to tell you what to do because it wouldn't work anyway. So nobody tried to influence me one way or the other. There were only a few patients who suggested that doctors tried to exert what was viewed as unwelcome or inappropriate influence. One respondent, who remarked in one portion of the transcript that she did not feel pressured, later reported, The doctor sort of made a plug. He said, you know, if people like you refuse to get into this, we're never going to get anywhere. Another respondent indicated that he felt pushed by one doctor to sign a consent form for a particular type of infusion treatment. They say, well, go ahead and sign it so we can start you on the process. And I said, well, I want to read it. And he said, have you signed it yet? And I said, I haven't read it yet. Oh, OK, well, we need you to sign it and then make a copy and we'll just let you read it afterwards. And I thought, what is going on? I mean, they had never ever kind of pushed it like that. Almost all patients reported that they had been told they could leave the research project at any time and that they believed that they could leave at any time. One respondent said, they always told us all the way along, anytime you don't feel happy with this, we can quit. They said, if you don't feel like you want to continue, you can quit anytime. There was no pressure on or nothing. Similarly, it was made very clear up front and then in the original package of material that they had at any point in time for any reason I wanted, you know, I didn't even have to have a reason. I could withdraw with no problem. For some participants, the question of withdrawing seemed almost foreign because there was such trust in the research process. One respondent said, the thought of withdrawing never entered my mind. I was going to let them make the decision because they were the ones that were watching the cancer. I wasn't the expert. If they thought it was working, that was fine. One respondent who was in the military believed that continued participation was required. Another respondent about to undergo a bone marrow transplant reported being pressured both to enrol and to continue participation in a clinical trial. They were really pushing this procedure. Note, a drug to help raise white blood cell counts and note. It was very obvious to me that they wanted people to sign up for this bad and I did not want to upset my doctor. You know, I'm totally helpless. I'm in his hands and so part of it was I wanted to keep him happy and there was some pressure. As described earlier, several patients in therapeutic research identified an intense desire to have some type of treatment. This not only influenced their decision to enrol but also to remain in a research project. One respondent stated that participating in research was through necessity. The thought never entered my mind that I would withdraw from this program. Such sentiments also seem to influence patients' desires to find research projects for which they might be eligible. I said if something comes up that you think will benefit me, let me know. I wanted to be on that trial bad enough to where I gave in to the pressure. End of section 77. Section 78 of Final Report of the Advisory Committee of Human Radiation Experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Recording by Gillian Henry. Final Report of the Advisory Committee on Human Radiation Experiments. Contemporary Projects, Chapter 16, Part 4. Discussion. Limitations. Although we were able to involve different types of hospitals from five different areas across the country in this study, only 16 hospitals were included in our sample. We have no way of knowing whether our findings would have been different if we had interviewed individuals at other hospitals. Similarly, we interviewed only medical oncology, radiation oncology, and cardiology patients who were not hospitalised but were receiving their care at outpatient clinics. Most of them were white and many were more than 60 years of age. It is quite possible that other types of patients would have answered some questions differently from our patients and that healthy research subjects might have had different attitudes, beliefs or motivations for participation than patients likely to have serious illnesses did. In the in-depth interview component of the study, only people who believed they were or had been research participants were included. The responses of people who had chosen not to participate in research, presumably, would be quite different. It should not be assumed, therefore, that our findings necessarily apply to the entire research enterprise. An important research question in this project was the degree to which present-day patients know whether or not they are research participants. To answer this question, we interviewed patients and asked them whether they believed they were or had been participants in research, and then, with their permission, we checked their records for evidence of research participation. Although this approach provides an estimate of the degree to which present-day patients know or remember if they are research subjects, this estimate is likely to be very rough for two sets of reasons. First, interviewing patients in the way we did may not be the most accurate way of gauging their own understanding of participation in research. This is because they were often approached in a busy clinic setting by an interviewer they did not know. It is also likely that these patients were under stress at the time of the interview, either because of their upcoming appointment with the doctors or because of the very illnesses that brought them to the clinics. In addition, because of necessity, the brief survey was designed to take only five to ten minutes to complete. We asked patients only about current or former research participation with single questions, rather than a series of questions designed to more completely capture those patients who had experience with research. Moreover, following our review of the medical and research records, we did not go back to patients and ask them questions about research once we had an understanding of their medical history and documented research experience. Second, despite significant attempts to gather information from multiple sources, the method of abstracting medical and research records we used may not have been comprehensive enough to locate all relevant evidence of research participation. For example, records of research may not be retained at the same institution in which the brief survey was conducted, or research participation may have been in the distant past and records may no longer be available. A related problem is that some patients may have been enrolled in studies that purposely do not keep records of participation. For example, studies where confidentiality is paramount. Finally, while trained abstractors examined records for all patients, health professionals on the advisory committee staff only reviewed records where patients' responses differed from the results of the initial records review conducted by the trained abstractors. Health professionals had only a one-to-two-day window to perform this confirmatory search of documentation at each institution, and thus were not always able to review relevant records because they were unavailable on short notice. Because of these reasons, we do not know the degree to which our estimates are accurate regarding the proportion of patients whose responses about research participation differed from what we found in records. A striking finding from this study is the frequency with which people with cancer and heart disease appear to come in contact with biomedical research in the course of their medical care. Notably, nearly 40% of the patients we talked with either believed they were or had been subjects in research, had records that showed that they were, reported that they had been offered the opportunity to be in research but had declined. Moreover, most patients thought that medical research was a good thing. They had favorable attitudes towards medical research generally. They believed that research did not involve unreasonable risks, and they believed that medical research usually or always advances science. Patients who are or had been participants in research had even more positive attitudes about research than those who had not. There was evidence in this study that many patients feel free to refuse when physicians and researchers ask them to become research subjects. Nearly 200 patients told us that they had been offered an opportunity to participate but had declined. Moreover, 40% of these patients had chosen at some other time to participate in research, indicating that at least some patients are discriminating in terms of the circumstances under which they are willing to participate in research. There also was little evidence that patients felt coerced or manipulated by healthcare providers or scientific investigators to participate in research. When we asked patients who were subjects if they had felt pressured by others into becoming research participants, these patients subjects overwhelmingly said no. Not only did they give the impression that the initial decision to enter a research project was theirs, but many also informed us that they had been told frequently by the investigators that they could drop out of the study at any point and the patients believed that this was so. Although the vast majority of both African American and white patients held favorable beliefs about research, such beliefs were held less often by patients who are African American. Specifically, as compared with white patients, African American patients were more likely to believe that people are pressured into research and more likely to believe that research poses unreasonable risks. These findings together suggest that for a small number of patients distrust as a result of the troubled historical experience of African Americans in research, as exemplified by the Tuskegee syphilis study may persist. We learned a great deal from this project about why patients choose to be in research. The overwhelming majority of the patients we interviewed who were participants in research were subjects in studies investigating medical treatments. Almost all of these patients said that they had enrolled in research because they thought it offered them their best chance of personal medical benefit. Moreover, for many of them, their doctors had recommended it. Often these patients had very serious illnesses and had tried many treatments unsuccessfully. The opportunity to be in research offered them hope that improvement might still be possible. Many of these patients specifically said that they had no choice but to participate. They had tried everything else to improve their condition and nothing else had worked. These patients felt constrained to participate because of their medical situation, not by their providers or the research investigators. Not surprisingly then when asked to describe the research project they were in, most of the patient subjects we talked with described the project as part of their therapy. Although when asked, these patients appeared to clearly understand which interventions were associated specifically with the research. They also conceived of the research treatment and despite the recognition by most of these patients that the goal of the enterprise of medical research generally was to advance science. When asked about their own specific project they often believed that the project would benefit them. It is likely that in some and perhaps in many of these cases it was indeed in the patient's medical best interest to be enrolled in a research project. As demonstrated by the recent push for access to investigational drugs on the part of people with HIV infection and other serious illnesses where there may seem to be no truly efficacious standard therapies, many patients believe that their best chance of extending life is to take treatments that are still experimental. In some cases, patient subjects were participating in treatment studies involving agents available only through research because their illnesses may have had no known efficacious treatments. From the perspective that holds extending life to be the primary concern it would be in the patient's best interests to be in the research. It is a separate issue whether participation in research is in a patient's overall best interests. Investigational interventions for devastating life threatening illnesses may be a patient's best chance, however small, of extending life. However, this chance may be at the expense of the person's ability to function and enjoy life for the time affected by participation in the research. Furthermore, the history of experimentation demonstrates that such therapies might also shorten life rather than extend it. Unfortunately, we did not pursue whether these sorts of trade-offs were clearly understood by the patient subjects we interviewed. In Chapter 15 we report some data from the RPRP that bear on this question. That patients viewed their participation as being in their best interests is consistent with patients' profound trust in their physicians on whom they depend as their lifelines and who they could not imagine offering something not in their best interests. From several patients the belief that their doctors are the experts and that they know best what would be helpful. If a doctor recommended or even offered research patients were certainly more inclined to decide to participate. The trust that patients placed in their physicians often was generalised to the medical and research community as a whole. Patient subjects frequently expressed the belief that an intervention would not even be offered if it did not carry some promise of benefit. Many certainly assumed that the intervention would not be offered if it posed significant risks. It was largely because of this trust that most patient subjects considered the consent process somewhat incidental to their decision to participate in research. When asked almost all patients reported that they had been provided with information, their questions had been answered and that they had been satisfied with the consent process. Nevertheless, doctors' recommendations and patients' own beliefs that the research was their best chance or even their only hope made the research an obvious decision for many patients and the consent process and consent form were viewed as somewhat of a formality. This framing of research as therapy is consistent with the very language used to describe research projects. We learned that patients attach very different meanings to the different terms associated with medical research. Experiments are considered by patients to involve unproven treatments of greater risk often invoking the image of human beings as guinea pigs. While terms such as clinical investigation or study convey less uncertainty to patients and a greater chance of personal benefit. The design of this study does not allow us to assess whether patients' expectations of benefit from their therapeutic trials were appropriate for the particular studies in which they were enrolled or whether their expectations were exaggerated or unrealistic. Moreover, if patients' expectations were exaggerated in some way, we have no evidence to discern whether patients overestimated benefit themselves or whether it was investigators who suggested that the research held more promise than was warranted. It is understandable that patients with poor prognoses may read hope into even the slimmest possibility of benefit. It also is understandable that some physicians uncomfortable with having little to offer their seriously ill patients might at such times inadvertently impart more hope than simple facts strictly speaking warrant. Hope is a delicate and precious commodity for those with life-threatening illnesses. For clinicians, the balance between support of that hope and honesty is often difficult. At the same time, however, there is a world of moral difference between a physician emphasising even inappropriately slim chances in order to bolster waning hope and physician emphasising slim chances in order to meet a recruitment goal for a clinical investigation. Feeding hope at the expense of candour is one thing. Exploiting the desperation of those whose lives hang in the balance is another. Here again, our data are silent. We cannot know insofar as physicians contributed to unrealistic expectations among these patient subjects how often this was the result of well-meaning reassurances or self-interested misrepresentations. It seems very much related that we found that a small proportion of patients believed they were subjects in research when it appeared they were not and other patients believed they were not research subjects when records suggested that they were. These confusions about whether a patient was in research occurred almost exclusively in or thought they were in research investigating potential therapeutic interventions. However we found that these patients covered the full range in terms of education, income, sex and race. They came from all three medical specialties studied and all types of hospitals. At least three quarters of the patients who apparently were mistaken when they reported they were not had actually signed consent forms authorising participation in research. In addition to the limitations of our methods described earlier in the chapter we can only speculate as to why the discrepancy exists between patients' perceptions and their records. Some patients may not have understood our question and may in fact have known they were research subjects all along. Other patients may not have understood what they were doing when they signed the consent form perhaps believing that it was a consent for treatment. Still other patients may have had an adequate understanding that they were consenting to participate in research at the time they signed the form and then later forgot. This last explanation is not as troubling as the second in that it suggests the possibility that in at least some cases valid consents were initially obtained but it does raise questions about the meaningfulness of these patients right to withdraw from research. Such questions are obviously more meaningful in ongoing projects that involve continuing exposure to potential risk in contrast to those studies where research participation is less burdensome such as studies involving routine follow-up or only a minor change in a regular therapeutic regimen. In this case in clinical research that the participation of ill people in research and the medical treatment they receive for their illnesses are identical. When this occurs it is not surprising that some patients conflict their being in research with therapy to the point that they no longer understand or remember that they actually are in a research project. Ironically it may be especially when patient subjects feel well cared for that they are most likely to feel like a patient only and not like a research subject. At the same time many patient subjects told us of being reminded by research staff that they could leave the project at any time for any reason. It seems doubtful that the patients we interviewed whose self-report of participation was not consistent with research records had such an experience. Although most of the patients we interviewed listed a chance at medical benefit as a reason for participating in research many patients also said that they had participated in research to help others. Some patients described the willingness to participate in research as a civic duty. Others wanted to help members of their own families at risk for the same conditions. And still others saw being in research as a means of making a shortened life expectancy more meaningful. Participants in survey research and similar research projects were especially likely to say that they had joined in part because there was no reason not to do so but also because they hoped they could help others or advance science by doing so. Several patients in therapeutic research who appreciated that there was only a slim chance that the research would provide them with personal benefit offered that as a result of their participation they hoped at least that someone down the road would be better off if not themselves. This willingness of patients to be altruistic should be tapped explicitly when recruiting participants for research since it might help to underscore for patients that the primary objective of research is to create generalizable scientific knowledge rather than simply to offer them a chance for some medical benefit. In the end it is only the benefit of furthering knowledge that can be honestly guaranteed to a potential research subject. End of section 78. Section 79 of Final Report of the Advisory Committee on Human Radiation Experiments This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer visit LibriVox.org recording by Abahi in June 2019. Final Report of the Advisory Committee on Human Radiation Experiments Discussion of Part 3 The Committee undertook the efforts described in Part 3 of this report in order to gain insight into the current status of protections in human radiation research and research with human subjects generally. An important finding of Part 3 is that with respect to the rights and interests of human subjects there appear to be no differences between radiation research and other research. Compared with what we have learned about the 1940s, 1950s and 1960s, there have been many changes in the climate and conduct of human subject research. The most obvious change is the regulatory apparatus described in Chapter 14 which was not in place in that earlier time. The rules of research ethics are also more articulated today than they were then as exemplified by the evolution of the concept of informed consent. Although the basic moral principles that serve as the underpinning for research ethics are the same now as they were then the issues of greatest concern to us today are different or have taken on a different cast from those of earlier decades. In our historical inquiry for example, we concentrated on cases that offered subjects no prospect of medical benefit. They were instances of non-therapeutic research in the strictest sense. That is, these were experiments in which there was never any basis or expectation that subjects could benefit medically. Both the design and the objectives precluded such a possibility. Most of the human radiation experiments that were public controversies when the advisory committee was appointed were of this type. The basic moral concern they raised was whether people had been used as mere means to the ends of scientists and the government. This would have occurred if the subjects could not possibly have benefited medically from being in the research, and they had not consented to disuse of their person. As we noted in chapter 4 the ethical issues raised by research that is non-therapeutic in this strict sense are stark and straightforward. Because risks to subjects cannot be offset by the possibility that they might benefit medically, there is rarely any justification for non-therapeutic research that puts subjects at significant risk. Participation in such research is always a burden and never a benefit to the individual subject, making questions of justice straightforward as well. And, at least theoretically, there are no subtleties involved in disclosing to potential subjects that they cannot possibly benefit medically from participating in the research, although problems do emerge concerning what incentives are appropriate to induce people to become research subjects, when consideration of altruism aside, it is otherwise not in their interests to do so. Today we still conduct non-therapeutic medical research on human subjects. Much research in physiology offers subjects no prospect of medical benefit, as does every protocol that calls for normal controls. Although non-therapeutic research frequently involves subjects who are healthy, it also often involves patient subjects as well. It is, of course, still appropriate to be concerned about the ethics of such research as it is with all research. For example, we were particularly troubled in our research proposal review project by documents that suggested that adults of questionable competence were being used as subjects of research from which it appeared they could not benefit medically and where the authorization for this use was unclear. Much research involving human subjects does not, however, fit this non-therapeutic paradigm. Many of our most pressing ethical questions concern research that raises at least the specter of potential medical benefit to the patient subject. For example, unlike the plutonium experiments with hospitalized adults, or the iodine-131 experiments with hospitalized children in which there was no possibility that the patient subjects could have benefited medically, in the modern Phase 1 trial, which is conducted to establish toxicity, there is at least the possibility of therapeutic benefit, however slim. Thus, although Phase 1 trials often impose significant burden and risk on subjects, they are not non-therapeutic in the strict sense. And, in contrast with Phase 1 trials, in much research involving patient subjects, there is a real prospect that subjects will benefit medically from their participation. In many of these cases, being a research subject is clearly in the medical best interests of the patient. As Otto Gutentag observed in the 1950s, C Chapter 1, it is the possibility of medical benefit that creates much of the moral tension in human subject research. Physician researchers are often torn between the demands of a research project and the needs of particular patients. Today this tension has taken on special significance with the immense growth of research at the bedside and the frequency with which the medical care of seriously ill patients is intertwined with clinical research. In our subject interview study, for example, at least a third of the patients interviewed had some contact with medical research. It is these considerations that led us to focus the subjects reported on in Part 3 and particularly the SIS on research involving patient subjects. The committee regrets that we did not have the resources to conduct a similar study with subjects who are not also patients. It would have been particularly useful to have conducted such a study with subjects who are military personnel not currently in medical care. This would have allowed us to find other important sources of tension in the ethics of research including the tension between giving orders and soliciting consent and between occupational monitoring and research. Although the SIS and the RPRP employed radically different methodologies and were directed toward different research questions, both projects speak to the ethical issues raised by the research in a medical context. A context dominated by the human needs to be healed and to heal. The findings of the SAS underscore what other smaller studies also have identified that patient subjects generally decide to participate in medical research because they believe that being in research is the best way to improve their medical condition. In the SIS we could not determine whether the patients had unrealistic expectations about how likely it was that they might benefit from being in research or in what form that benefit might take. Other empirical studies suggest that some subjects do have an inadequate, sometimes exaggerated understanding of the potential benefits of the research in which they are participating. In the RPRP we reviewed consent forms that appeared to over-promise what research could likely offer the ill patient and underplay the effect of the research on the patient's quality of life. These were the kinds of disclosures that could easily be interpreted by a patient desperate for hope as offering much more than realistically could be expected. Not surprisingly this problem was the most acute in certain Phase 1 trials that, while not being non- therapeutic in the strict sense, appeared to offer only a remote possibility of benefit to the patient's subject. In oncology, for example, it is estimated that in only about 5% of subjects enrolled in Phase 1 chemotherapy studies, thus the tumor responds to the drug and it is often unclear even then what the tumor response means from a patient's point of view. To say that there is no prospect that the patients might benefit medically is questionable, there are enough cases of patients being helped in Phase 1 trials to make such a stark claim problematic. Beneficial effects of Phase 1 trials have a very low probability but do occur. At the same time, however, any suggestion of the possibility of benefit has the potential to be magnified many times over by patients with no good medical alternatives. It is understandable that physicians, faced with the prospect of little or nothing to offer seriously ill patients may sometimes impart more hope than the clinical facts warrant. At the same time, however, desperate hopes are easily manipulated. Consider, for example, a recent report of a small study of patient subjects participating in Phase 1 clinical oncology trials. Despite the predictably low likelihood of medical benefit for subjects in Phase 1 trials, all of the patient subjects surveyed about their reasons for participating said their decision was motivated in large part by the possibility of therapeutic benefit and nearly three quarters cited trust in their physician as motivating their decision to participate. Only one third listed altruism as a major motivating factor. These results support what we found in the SIS, that patient subjects view research participation as a way of obtaining the best medical care, even when participating in research holds out very little prospect of direct benefit. This phenomenon, which is especially relevant when some subjects receive a placebo as a part of the research, has been dubbed the therapeutic misconception. This phenomenon is not confined to patient subjects perceptions of benefit from research. At least one study has shown that physician investigators also overestimate the potential benefits to subjects participating in Phase 1 oncology trials. One of the most powerful themes to emerge from the SIS is the role of trust in patients' decisions to participate in research, a finding that has been observed in other studies as well. It was common for patients in the SIS to say that they had joined a research project at the suggestion of their physician and that they trusted that their physician would never endorse an option that was not in their best interest. This trust underscores the much role of physician investigator, whose duties as a healer and as a scientist inherently conflict. This trust that patients place in their physicians often is generalised to the medical and research community as a whole. Some patients expressed faith not only in their doctors but also in the institutions where they were receiving medical care. These patients believed that hospitals would never permit research to be conducted that was not good for the patient's subjects. The trust that patients have in physicians and hospitals underscores the importance of the committee's concern based on our review of the documents in the RPRP that IRBs may not always be properly structured to ensure that the medical interests of ill patients are adequately protected. In some cases, the scientific information to make such judgments was not included in the documents we received. Even with adequate information IRBs may lack sufficient expertise to evaluate the science or implications for medical care of particular proposals. As we heard from some IRB chairs they may also lack the staff or the respect and authority within their institutions to function adequately to protect subjects. The theme of trust discerned in the SIS also has implications for how properly to view the role of informed consent in protecting the rights and interests of human subjects. For many of the patients who based their decision to be in research on their trust in their physicians, the informed consent process and the informed consent form were of little importance. IRBs conserve the interests of these patients best by being vigilant in their review of risks and benefits and attending to questions of fairness in the selection of subjects. On the other hand, we also found in the SIS that sizable numbers of patients had refused offers to participate in research and that some patients who had consented to be research subjects had made efforts to learn what they could about the research opportunity. For these patients the informed consent process likely served an important moral function. From these seemingly conflicting results we can conclude both that the informed consent requirement is crucial to protect the autonomy rights of those potential subjects who choose to exercise them, but that it is naive to think that informed consent can be relied upon as the major mechanism to protect the rights and interests of patient subjects. Taken together, the results of our two projects suggest that it is important to correct the deficiencies identified in the RPRP with respect to informed consent. Our results also underscore, however, the importance of an IRB review that focuses on whether the proposed research is a reasonable, ethically acceptable option to offer the patient in light of available alternatives and the risks and potential benefits of the proposed research for the subject, including impact on quality of life. An alternative, the practice of adding detail to consent forms as a way to further informing potential subjects who often have a difficult time understanding risks, benefits and purposes of research is unacceptable. By confusing subjects, it offers less rather than greater protection. For the many patients who continue to rely on the expertise and goodwill of physicians and hospitals in deciding whether to participate in research, rigorous review on the part of IRBs and rigorous commitment on the part of physicians to honour the faith entrusted to them are the important protections. The SIS and the RPRP also both speak to the current confusion between research and standard care in medical practice. The same therapy that is part of a research protocol and therefore must receive IRB approval can proceed outside of the research setting and not be subject to IRB oversight. This leads to understandable confusion on the part of subjects as to whether they are participating in research, receiving standard care or some combination. It is thus perhaps not surprising that research subjects occasionally seem unaware of their participation in research, even when there is evidence that they have signed consent forms. This finding was observed in the SIS, though the methodology of the study did not allow us to probe the reasons some subjects appeared unaware of their participation. The confusion between research and alternative medical interventions is mirrored in the language used to communicate to patients in the informed consent process and in the language of patients themselves. In the SIS, the patients surveyed viewed experiments as involving unproven treatment of greater risks while clinical investigation or study conveyed less uncertainty and were perceived as offering a greater chance of personal benefit. None of the consent forms we reviewed in the RPRP used the term experiment. Conclusion In addition to the role they played in helping the advisory committee come to our conclusions, the RPRP and SIS should be understood as adding to the body of research undertaken to try to understand the strengths and weaknesses of the system to protect the rights and interests of human subjects. In the end, patients' reasons for participating in research must more accurately reflect the benefits they may reasonably expect. Altruistic motivation can be more fruitfully tapped, both for the benefit it provides to the advancement of science and to underscore for patients that the primary objective of some research is to create generalizable scientific knowledge, rather than to offer personal benefit to them. Subjects are much more likely to have a positive view of biomedical research if they feel they understand what prospects research holds for them. The good news in the endeavor of human subject research is that subjects are willing to participate and in the process entrust their care to researchers. However, that trust cannot be taken for granted, as it sometimes has been in our history. Increasingly, it is being argued that it is generally advantageous for patients to participate in research. The distinction between standard care and research, if it was ever clear, is viewed as growing dimmer all the time. As a consequence, the debate over subject selection has changed entirely. As we discussed in Parts 1 and 2, in the past the central concern was that certain populations considered vulnerable to exploitation because of their relative powerlessness were inequitably bearing the burdens of the risks of research. Today, the concern is that the same populations may have inequitable access to research and therefore individuals and the communities of which they are apart may be denied a fair share of the benefits of research participation. While this is a valid moral concern, the results of the SIS and the RPRP suggest that it remains important to be attuned to issues of vulnerability. While patients with serious illnesses may also stand to gain the most from participating in medical research, they also are among the most vulnerable to its risks. It also is important to underscore the finding in the RPRP that in both studies involving minimal risk and those involving greater risk, research with ill-patient subjects can proceed ethically and consent can be properly obtained. The research enterprise is too important to jeopardize by inadequate protections for subjects. Tensions and potential conflicts exist throughout the research process and so we must be sure to acknowledge and address them squarely. This is the goal of the next and final part of the advisory committee's report. End of section 79 Section 80 of Final Report of the Advisory Committee on Human Radiation Experiments This is a LibriVox recording All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org Recording by Avayee in June 2019 Final Report of the Advisory Committee on Human Radiation Experiments Section 80 Part 4 In two terms with the past, looking ahead to the future. Part 4 Overview In Part 4 we present the overall findings of the advisory committee's inquiry and deliberations and the recommendations that follow from these findings. In Chapter 17 findings are presented in two parts. First for the period 1944 through 1974 and then for the contemporary period. These parts in turn are divided into findings regarding biomedical experiments and those regarding population exposures. We begin our presentation of findings for the period 1944 through 1974 with a summation of what we have learned about human radiation experiments. Their number and purpose, the likelihood that they produced harm and how human radiation experimentation contributed to advances in medicine. We then summarize what we have found concerning the nature of federal rules and policies governing research involving human subjects during this period and the implementation of these rules in the conduct of human radiation experiments. Findings about the nature and implementation of federal rules cover issues of consent, risk, the selection of subjects and the role of national security considerations. Our findings about government rules are followed by a finding on the norms and practices of physicians and other biomedical scientists for the use of human subjects. We then turn to the committee's finding on the evaluation of past experiments in which we summarize the moral framework adopted by the committee for this purpose. Next we present our findings for experiments conducted in conjunction with atmospheric atomic testing, intentional releases and other population exposures. The remaining findings for the historical period address issues of government secrecy and record keeping. There is an asymmetry in our findings on human radiation experiments and intentional releases. In both cases we discuss their number and purpose, the likelihood that they produced harm and what is known about applicable government rules and policies. In the case of human radiation experiments we also have a finding on the benefits to medicine and thus to all of us that human radiation research during this period produced. We do not however have a corresponding finding on the benefits of the intentional releases of the period, benefits that would presumably have been to the national defense and thus again to all of us. Although the members of the committee are positioned to comment on contributions to medicine and medical science, we do not have the expertise to evaluate contributions to the national defense and thus could not speak to this issue. Our findings for the contemporary period summarize what we have learned about the rules and practices that currently govern the conduct of radiation research involving human subjects, as well as human research generally, and about the status of government regulations regarding intentional releases. Chapter 18 presents the committee's recommendations to the Human Radiation Interagency Working Group and to the American people. The committee's inquiry focused on research conducted by the government to serve the public good, the promotion and protection of national security, and the advancement of science and medicine. The pursuit of these ends, today as well as yesterday, inevitably means that some individuals are put at risk for the benefit of the greater good. The past chose us that research can bear fruits of incalculable value. Unfortunately, however, the government's conduct with respect to some research performed in the past has left a legacy of distrust. Actions must be taken to ensure that, in the future, the ends of national security and the advancement of medicine will proceed only through means that safeguard the dignity, health, and safety of the individuals and groups who may be put at risk in the process. The needed actions are in four dimensions. First, the nation must provide for appropriate remedies as it comes to grips with the past. Second, the nation must provide improved means to better ensure that those who conduct research involving human subjects act in a manner consistent with the interests and rights of those who may be put at risk, and consistent with the highest ethical standards of the practice of medicine and the conduct of science. Third, the nation must ensure that special care is taken to prevent abuses in the conduct of human subject research and environmental releases in a context where these activities must occur in secret. Fourth, the nation must ensure that records are kept so that a proper accounting can be made to those who are asked to bear risks, particularly when any or all of the risk-taking involves secrecy. Moreover, these records should be made available to the public at large on a timely basis, consistent with legitimate national security requirements. The committee's recommendations address these four areas, remedies for the past, practices to govern the future of biomedical experimentation, practices to govern the future exposure of citizens to biomedical research or environmental releases from secret activities and provisions for record keeping and public access to records. We wish to note here the limits of our framework for remedies for past harms or wrongs for subjects of human radiation experiments. Footnote. In accordance with our charter, these recommendations apply to human radiation experiments conducted from 1944 to 1974 that were supported by the government, whether the support was in the form of funding including funding for data gathering in conjunction with exposure of patient subjects to radiation or other means such as the provision of equipment or radioisotopes and regardless of whether the research was performed by federal employees or non-federal investigators. Although we focus here on human research involving exposure to radiation, the moral justification for these recommendations is not specific only to experiments involving radiation. End footnote. First, we are addressing questions of remedies from the perspective of what ethically ought to be done. We recognize that some of the remedies we propose, including financial compensation, may not be available under current federal law. To the extent that such remedies are not available under current law, we encourage the administration to work with Congress to develop such remedies through legislation or other appropriate means. Second, the committee has focused on past experiments in which there was no possibility that subjects could derive medical benefit from being in the research or in which the potential for this benefit is in dispute. These were the experiments that raised the greatest public concern. They were also the experiments that raised the greatest concern for most members of the committee when we considered the 1944 to 1974 period. This was a time, as noted throughout this report, when it was common for physicians to use patients as research subjects without the patient's knowledge or consent. It was also a time, however, when physicians needed considerable moral authority both by patients and by society to decide for patients what medical treatments they should receive. This authority extended, as well, to deciding whether a patient should be a subject in therapeutic medical research, provided that this decision was based on a good faith judgment by the physician that it was in the patient's medical best interest to be a subject in the research, and thus that any risks of the research were acceptable in light of the possibilities of medical benefit. Even at the time, however, physicians did not have the moral authority to use patients without their knowledge or consent as subjects in research in which there was no expectations that they could benefit medically. The committee appreciates that simply because the moral context of the doctor-patient relationship during the 1944-1974 period was different from today's this does not mean that all therapeutic research was always or even often conducted in an ethical fashion. We also appreciate that the risks of therapeutic research were often considerable and that it is likely that some patient subjects were harmed unnecessarily as a consequence. However, the moral problems presented when people in the 1944-1974 period were used as subjects of research from which they could not benefit medically are both more straightforward and more compelling. We therefore felt obligated to expend our limited resources on historical and moral analysis of these kinds of experiments. We do not address whether or under what conditions remedies should be provided for injuries or offenses related to research that offered a plausible prospect of medical benefit to subjects and believe that work to others. Third, even in those experiments where there was no prospect of medical benefit limited committee resources and the overall committee mandate precluded the type of fact-intensive individual investigation that would give rise to a recommendation of compensation in individual cases. The committee did not have the ability to locate and evaluate the research and medical records of countless individual subjects. As a consequence, for example, we were not able to make judgments about whether, in individual cases, subjects had suffered physical harm attributable to their involvement in research. Fourth, we note that the committee was not unanimous in its decision to make a recommendation for remedies for people who were subjects in experiments that offered them no prospect of medical benefit, but who were not physically harmed as a consequence. Recommendation three. Three committee members elected not to support this recommendation. The entire committee believes that people who were used as research subjects without their consent were wronged even if they were not harmed. Although it is surely worse, from an ethical standpoint, to have been both harmed and wronged than to have been used as an unwitting subject of experiments and suffered no harm, it is still a moral wrong to use people as a mere means. Although what we know about the practices of the time suggests, it is likely that many people who were subjects in non-therapeutic research were used without their consent or with what today we would consider inadequate consent, in most of these cases we have almost no information about whether or how consent was obtained. Moreover, in most of these cases the identities of the subjects are not currently known. Even if considerable resources were expended, it is likely that most of their identities would remain unknown. The committee is not persuaded that even where the facts are clear and the identities of subjects known, financial compensation is necessarily a fitting remedy when people have been used as subjects without their knowledge or consent but suffered no material harm as a consequence. The remedy that emerged as most fitting was an apology from the government. The committee struggled with and ultimately was divided on the issue of whether to recommend that the government extend an apology under the circumstances just described. While all members agreed that a goal of the committee's recommendations is in the words of one member to find the nation's wounds, we disagreed about how best to accomplish that end when debating whether we should recommend such an apology. Our deliberations were complicated by what we all agreed was a murky historical record. In the case of some experiments, there was evidence of some disclosure or some attempt to obtain consent and the issue emerged as how poor these attempts must be for an apology still to be in order. In other cases, there was simply too little documentary evidence to draw any conclusions about disclosure or consent. In most cases, as noted above, the identities of subjects are unknown and are unlikely to be uncovered even with an enormous expenditure of resources. The committee members who concluded that it was not appropriate to recommend that the government apology be extended did not all reach this conclusion for the same reasons. Among the reasons put forward were that it would be impossible to craft the recommendation for an apology in such a way as to avoid the divisiveness that could result from apologizing to some, but not all of those who view themselves as victim of this kind of human radiation experiment. There was concern that if the criteria for who should receive an apology were too narrow, some people would resent not qualifying for an apology. Conversely, if the criteria were too broad and included large numbers of people, the generality of the apology would diminish its meaningfulness. It was also argued that a recommendation for an apology should not be made because of the difficulties in crafting the criteria for eligibility in the face of an incomplete historical record. Another reason for not recommending an apology was that during the 1944 to 1974 period many people were used as subjects of research that did not involve radiation for which there was no prospect of medical benefit and consent was not obtained from them and these people would not be included in a recommendation from us for an apology. The committee members who favored an apology took the position that justice requires that an apology from the government is due in research that it sponsored, where it can be determined that an apology is deserved and the identities of subjects who were wronged can be known. They do not believe that the apologize rests on the likelihood that it will lead to more healing than divisiveness. Rather, these committee members hold that an apology is a just remedy for those who were wronged and that it should not be withheld only because there are other cases that are likely to have been morally similar but for which a recommendation of an apology could not be made because the evidence was unclear or unavailable. A specific apology in those cases where the facts are clear today would not for these committee members preclude apologies being extended to other subjects in the future should new information come to light. All committee members agreed that it was appropriate that the subjects of the experiments at the Fernald State School in Massachusetts receive an apology but divisions within the committee arose when we decided to determine how to differentiate them from the subjects of studies similar to those conducted at Fernald about which less is known in relation to disclosure and consent. Fifth, the committee notes that our recommendations for remedies are directed solely to the executive and legislative branches of the federal government. They are not recommendations for exclusive remedies intended to seek redress from other parties or the courts. Those who believe they or their family members have been wronged or injured should be free also to seek relief from appropriate institutions or from individuals. The committee does not intend to suggest the limiting of any rights to do so. Finally, the framework for remedies for former subjects of human radiation experiments that the commissioners in our recommendations limits the availability of compensation from the federal government to what is likely to be a small number of people. In developing the framework we were concerned about the impact of recommending criteria that would result in compensation in some cases but not in others. The committee sought and heard testimony from hundreds of witnesses over months of deliberation, many of whom were emotional and heart-rending in sharing their experiences. Often these witnesses expressed considerable anguish over the pain that they and their families suffer because of their belief that they have been or might yet be harmed and some advanced view that compensation is appropriate. It was very painful for the committee to recognize that often we had neither the resources nor the mandate to investigate all these compelling stories. The committee concluded that an appropriate service we could render was to shed light on this dark period in our history by articulating the historical record to the best of our ability. But it is equally important that the historical record having been spelled out we as a nation move forward. The most fitting way to acknowledge the wrongs and harms that were done to others in the past and to honor their contributions to the nation is for the government to take steps to ensure that what they experienced will not happen again. Thus, many of our recommendations are directed not to the past but toward the future. The committee calls for changes in the current federal system for the protection of the rights and interests of human subjects. These include changes in the interpretation of ethic rules and policies, in the conduct of research involving military personnel as subjects, in oversight, accountability and sanctions for ethics violations and in compensation for research injuries. Unlike the 1944 to 1974 period in which the committee focused primarily on research that offered subjects no prospect of medical benefit, our recommendations for the future emphasize protections for patients who are subjects of therapeutic research, as many of the contemporary issues involving research with the human subjects occur in this setting. We also call for the adoption of special protections for the conduct of human research or environmental releases in secret protections that are not currently in place. We also consider that regulations and policies are no guarantee of ethical conduct. If the events of the past are not to be repeated, it is essential that the research community come to increasingly value the ethics of research involving human subjects essential to the scientific enterprise. We harbor no illusions about the Pollyanna-ish quality of a recommendation for professional research. We ask that the biomedical research community, together with the government, cause a transformation in commitment to the ethics of human research. We recognize and celebrate the progress that has occurred in the past 50 years. We recognize and honor the commitment to research ethics that currently exists among many biomedical scientists and many institutional review boards. The scientists of the future must have a clear understanding of their duties to human subjects and a clear expectation that the leaders of their fields value good ethics as much as they do good science. At stake is not only the well being of future subjects, but also, at least in part, the future of biomedical science. To the extent that the future depends on public support, we must. There can be no better guarantor of that trust than the ethics of the research community. Finally, our examination of the history of the past half century has helped us understand that the revision of regulations that govern human research, the creation of new oversight mechanisms and even a scrupulous professional ethics are necessary, but not sufficient means to needed reform. Equal import is the development of a more common understanding among the public of research involving human subjects, its purposes and its limitations. Furthermore, if the conduct of the government and of the professional community is to be improved, that conduct must be available for scrutiny by the American people, so that they can make more informed decisions about the protection and promotion of their own health and that of the members of their family. It is toward that end that we close our report with recommendations for continued openness in government and in biomedical research. It is also toward that end that this report is dedicated. Some of what is regrettable about the past happened, at least in part, because we, as citizens, let it happen. Let the lessons of history remind us all that the best safeguard for the future is an informed and active citizenry. End of Section 80. Section 81 of Final Report of the Advisory Committee on Human Radiation Experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org Final Report of the Advisory Committee on Human Radiation Experiments Coming to Terms with the Past Looking Ahead to the Future Chapter 17 Part 1 Findings Findings for the period 1944 through 1974 Biomedical Experiments Finding 1 The Advisory Committee finds that from 1944 through 1974 the government sponsored by providing funding, equipment, or radioisotopes several thousand human radiation experiments. In the great majority of cases the experiments were conducted to advance biomedical science. Some experiments were conducted to advance national interests in defense or space exploration and some experiments served both biomedical and defense or space exploration purposes. These experiments were conducted by researchers affiliated with government agencies, universities, hospitals, and other research institutions. Only fragmentary information survives about most experiments. Finding 2 The Advisory Committee finds that the majority of human radiation experiments in our database involved radioactive tracers administered in amounts that are likely to be similar to those used in research today. Most of these tracer studies involved adult subjects are unlikely to have caused physical harm. However, in some non-therapeutic tracer studies involving children, radioisotope exposures were associated with increases in the potential lifetime risk for developing cancer that would be considered unacceptable today. The Advisory Committee also identified several studies in which patients died soon after receiving external radiation or radioisotope doses in the therapeutic range that were associated with acute radiation effects. Review of available information indicates that the majority of the approximately 4,000 human radiation experiments in the Advisory Committee database involved the use of radioisotopes as tracers in research designed to measure physiological processes in either normal or diseased states. These experiments were not typically aimed at measuring the biological effects of radiation itself. However, information on the majority of experiments in our database was fragmentary and thus did not allow for detailed estimates of dosimetry or examination of issues of experimental design and subject selection. To supplement the information in our database and provide context to our analysis we independently reviewed archival documents from AEC mandated institutional local isotope committees. These local use committees were part of a larger AEC program that facilitated the distribution of radioisotopes for use in government sponsored human subjects research in the 1947 through 1974 period and involved the review of experimental risk on an individual basis to ensure that human uses of isotopes were within accepted risk standards of the day. We thus used these materials as an indicator of isotope use and regulatory practices at that time. While we recognize the limitations of the data available to us our evaluation suggests that most tracer studies conducted during the period 1944 through 1974 likely involved low doses that did not cause any acute or long term effects. The advisory committee cannot rule out however the possibility that some people were or will be harmed as a consequence of their involvement in these experiments. The committee did identify some non-therapeutic tracer experiments involving the administration of iodine 131 to children which may have raised the subsequent risk of developing thyroid cancer to levels that would be considered unacceptable today. Based on the average risk estimate for each experiment approximately 500 individuals to greater than minimal risk. The committee used a threshold of greater than or equal to one excess case of cancer per 1,000 subjects for categorizing experiments as greater than minimal risk. Combining the average risk estimates for each experiment this translates into an expected excess of 1.3 incident cases of thyroid cancer for the entire group. Fortunately unlike many other cancers, thyroid cancer is curable in more than 90% of cases. Therefore it is unlikely that even if cancers developed these exposures caused any premature deaths. Furthermore although there is strong scientific evidence that radiation doses delivered over a short period of time from external sources can result in increases in cancer incidents at specific sites comparable data suggest that the carcinogenic effects of isotope exposures are less than those of external irradiation. The difference in carcinogenic effect is thought to be due to the relatively low dose rate of the isotope exposure which allows for effective repair of radiation damage. One additional isotope study involving the administration of radio iron to pregnant women has been linked to a possible increase in cancers in children who were exposed in utero. However the small number of observed cancers as well as considerable uncertainties in the amount of radioisotope administered have made the determination of causality difficult. Finally the committee found some experiments where radioisotope exposures were associated with either acute or chronic physiologic changes of uncertain clinical significance. Pathologic evidence of kidney damage secondary to chemical and radiation toxicity in some patients injected with uranium and radiographic evidence of minimal bone changes in some long term survivors of plutonium injections. Studies that involved radiation doses in the therapeutic range were for the most part performed on patient subjects where there was at least arguably a prospect that the subjects might benefit medically from the exposure. However the TBI in experimental gallium treatments in which patients suffered symptoms of acute radiation sickness and died soon after treatment raised the question of whether their deaths were hastened by the radiation treatments. Resolution of this issue requires review of individual medical histories which the advisory committee could not undertake. Finding 3 The advisory committee finds human radiation experimentation during the period 1944 through 1974 contributed significantly to advances in medicine and thus to the health of the public. Human radiation research was essential to the development of new therapies such as the use of radioactive iodine to treat thyroid cancer, the use of phosphorus to treat blood diseases such as polycythemia vera and the use of radioactive strontium as a palliative in prostate and other cancers metastasized to the bone. Diagnostic uses of radionuclides developed during this period include scanning techniques to identify tumors and radiolabeling techniques that help evaluate a variety of cardiac diseases. The quality of images produced by external sources of radiation also improved dramatically between 1944 and 1974 making possible, for example, techniques such as balloon angioplasty to open occluded arteries. Finding 4 The advisory committee finds that some government agencies required the consent of some research subjects well before 1944. These requirements generally did not stipulate what was meant by consent, however, nor did they generally indicate whether investigators were obligated to disclose specific information on potential subjects. The government did not have comprehensive policies requiring the consent of all subjects of research including both healthy subjects and patient subjects until 1974. 4A Research involving healthy subjects In the 1920s the army promulgated a regulation concerning the use of volunteers for medical research. In 1932 the Secretary of the Navy required that subjects of a proposed experiment be informed volunteers. In 1942 the requirement that healthy subjects be informed volunteers was also articulated by the Committee on Medical Research which oversaw war-related research for the Executive Office of the President. In 1953 the principle of consent articulated in the Nuremberg Code in a top secret memorandum from Secretary of Defense Charles Wilson regarding human research related to atomic, biological and chemical warfare. This document is known as the Wilson memorandum. In 1954 this application of the Nuremberg Code was expanded by the Army Office of the Surgeon General as an unclassified policy for all research with human volunteers. A policy of requiring researchers to obtain consent was adopted by the Clinical Center the Research Hospital of the National Institutes of Health in 1953 by the Atomic Energy Commission in 1956 and by the Air Force in 1958. In the 1960s all branches of the Department of Defense promulgated regulations requiring the consent of healthy subjects and the Isotopes Distribution Division of the AEC included in its Guide for Researchers a requirement of consent from all subjects. In 1966 the Surgeon General of the Public Health Service issued a policy requiring the consent of all subjects of research conducted or funded by the PHS. Also in the late 1960s the Veterans Administration codified in its operating manual a requirement of consent from all research subjects. In 1972 the National Aeronautics and Space Administration adopted similar consent requirements although exceptions were made for certain subject populations such as astronauts. In 1974 the Public Health Service policy was promulgated as a regulation for all contracts and grants of the Department of Health Education and Welfare. The CIA did not formally adopt consent requirements until 1976 when an executive order mandated that it follow the 1974 regulations of DHEW concerning research involving human subjects. In an April 1947 letter the AEC General Manager stated the AEC's understanding that AEC contract researchers would inform patient subjects of the risks associated with a research intervention and that patient subjects express a willingness to receive the intervention. In a second letter written in November 1947 the General Manager specifically stipulated that the AEC require researchers to obtain informed consent in writing from patient subjects where substances known to be or suspected of being poisonous or harmful were given to human beings. In 1948 the AEC permitted the administration of larger doses of radioisotopes for investigative purposes but only with the patient subjects consent. In 1953 the NIH Clinical Center required consent from all patient subjects and specified that written consent was to be obtained from patient subjects involved in high or uncertain risk experiments. In the early 1960s several government agencies adopted consent provisions for investigational drugs. These requirements applied to some radioisotope experiments with patients. In 1965 the AEC required that consent be obtained from all subjects including patient subjects who were administered radioisotopes for experimental purposes except when it appeared not feasible or not in the patient's best interest. By 1967 the VA required the consent of all patient subjects. As noted in finding 4A above in 1965 the AEC required that consent be obtained from all subjects administered radioisotopes for experimental or non-routine uses. In 1966 the Surgeon General of the Public Health Service issued a policy requiring the consent of all subjects of research conducted or funded by PHS including patient subjects. Relations to this requirement were permitted for only certain kinds of social science research posing minimal risk. A 1972 NASA policy applied to all subjects of research presumably including patient subjects. By 1973 all branches of the military had promulgated regulations requiring the consent of patient subjects. In 1974 the PHS policy was promulgated as a violation for all contracts and grants of DHEW. Finding 5 The advisory committee finds that government agencies did not generally take effective measures to implement their requirements and policies on consent to human radiation research. Evidence of the implementation of the AEC's consent requirements stated in April and November 1947 letters from the general manager is slim. A document suggests that the April 1947 requirement for a signed statement from two physicians testifying to consent was satisfied in at least one case. However the advisory committee did not find evidence that this or other requirements stated in the 1947 letters were embodied as a provision of AEC contracts involving human subject research or otherwise routinely communicated to contract researchers. Further, there was no reference to the requirements stated in these letters or to the letters themselves in the written material disseminated to researchers by the AEC's program for distributing radioisotopes for human uses. Moreover requests for guidance concerning human use policies from investigators at AEC operated research facilities suggest that the 1947 requirements were not routinely disseminated. Subsequent requirements that healthy subjects be informed volunteers and that consent be obtained from seriously ill patients receiving higher doses of radioisotopes were more widely communicated. We have not been able to determine the extent to which they were actually implemented. Secretary of Defense Wilson's February 1953 top secret memorandum detailing requirements for research with human subjects was rewritten as an unclassified June 1953 directive from the Secretary of the Army. It is difficult to determine why these requirements were applied to some activities and not to others. For example, elements of some of these requirements appear to have been implemented in some experiments conducted in conjunction with atomic bomb tests and not in others. In 1954 these requirements were adopted by the Army Surgeon General as applicable to all research involving human volunteers. This 1954 statement was transmitted to contractors as a non-mandatory guide. However there is some evidence that the Army sought to include this statement as a condition in at least some contracts. Evidence of implementation of the NIH Clinical Center's 1953 policy requiring that information be provided to and consent obtained from all subjects is difficult to find. In most cases involving patient subjects, documentation would not have been required in writing. By contrast the use of healthy subjects in the clinical center required written consent and the normal volunteer program appears to have involved greater supervision to ensure that consent was obtained from these subjects. Finding 6 The advisory committee finds that from at least 1946 some government agencies had in place procedural mechanisms for reviewing the acceptability of risks to human subjects from exposure to radioisotopes. By 1974 the government had policies requiring review of the acceptability of risks to human subjects in other forms of research including research involving exposure to external radiation. Beginning in 1946 the Manhattan Project and from 1947 onward the AEC required some investigators seeking to conduct experiments using radioisotopes supplied by the government to have the risks to subjects reviewed by a committee at the institution where the work was to be conducted and in some cases by the AEC's subcommittee on human applications as well. The AEC required that local committees be composed of at least three physicians or researchers with relevant expertise regarding radiation safety and medical applications. By 1949 it was clear that this policy applied to all investigators using radioisotopes supplied by the AEC. In 1953 prior group review for risk was also begun at the NIH clinical center for proposed human research that involved unusual hazard. No such requirement applied to research funded by NIH but conducted at universities and other non-governmental research facilities until 1966 when the PHS required that all institutions establish a local peer review committee to evaluate the adequacy of the protection provided to human subjects in each proposal. This requirement was promulgated as an institutional policy by the DHEW in 1971. In 1953 by adopting the Nuremberg Code the Secretary of Defense in the Department of the Army endorsed several principles intended to minimize risk in research with human subjects at least in regard to the atomic, biological and chemical warfare experiments that were subject to this policy. In the DOD both the purpose of proposed research and the level of risk was directed to prior review through the military chain of command. This was previously required by the Navy at least from 1943 and the Air Force from 1952. However the extent to which these requirements covered particular research activities such as healthy subjects versus patients, radioisotopes versus external radiation and particular institutions such as contractors versus in-house research differs and is difficult to reconstruct. Also difficult to reconstruct is the extent to which the risk protection principles of the Nuremberg Code were implemented. In the mid-1960s concurrent with the adoption of regulations related to investigational drug testing the DOD and each military service adopted provisions requiring the establishment of a review board or committee to oversee proposed research projects involving new drugs. In some cases such as with the Air Force beginning in 1965 this committee also served to evaluate all other proposals involving human subjects. During this period the VA also established a review board mechanism for research involving new drugs and investigational procedures. Finding 7 The advisory committee finds that the government program of distributing radioisotopes for use in human subject research included procedures for the review of risk. These were widely implemented by researchers and institutions that used isotopes obtained from the AEC for human experimentation. However, there is no evidence that a parallel mechanism for reviewing the risks of research involving external radiation was in place. From its 1947 birth the AEC provided its policy to promote the peaceful use of radioisotopes required private institutions that wished to obtain radioisotopes for human uses including human experimentation as well as patient treatment to establish local review committees. These committees reviewed proposed human uses under guidelines provided by the AEC's own subcommittee on human applications of the advisory committee on isotope distribution policy. This AEC subcommittee reviewed these applications providing a second level of oversight of risk. By 1949 the AEC's own labs were required to establish local committees and to have human use applications reviewed by the same AEC subcommittee on human applications. The control of risk and the assurance of safety to all those involved including doctors and other health care workers was a primary purpose of the reviews. The advisory committee lacked sufficient evidence to determine whether the system was implemented in all of the many institutions that used government supplied radioisotopes for human subjects research or whether the system was always adhered to in any particular institution. In addition to providing for the review of research proposals the AEC dramatically increased the number of qualified personnel by offering training courses in the safe handling and use of radioisotopes. As individual procedures became routine the degree of review was lessened as specific institutions became more experienced more reviewing authority was delegated to them. The primary function of the system was to reduce the physical hazards of using radioisotopes not to enforce any policies regarding consent of subjects. C Chapter 6 Section 81


I get asked a lot how can we help this child who is struggling to go to school and it's a great question one I love to try and tackle with families with schools with all sorts of different people but it's the wrong first question if we've got a child who's not attending who's finding it really hard lots of anxiety and emotion around school then we need not first to think about well how do we overcome that we need to go back a step and try and understand the why why is this child finding school a struggle what is not working for them is it something to do with school is it something to do with home is it something internal is it something external the problem that we've got here is that emotionally based school avoidance or school anxiety or school phobia or whatever phrase we want to use and none of them feel right quite honestly whatever we're calling it a child who's struggling to go to school it can look quite similar from child to child but child a's reasons their issues their concerns their worries the things that's making it hard for them to go to school might be totally different than the concerns for child b but it kind of looks the same but if we treat them the same what might work for one child might not work for the other child a might find school totally overwhelming perhaps they are on the autistic spectrum and school for them is too noisy in every sense of the word and they find it really really challenging and the whole thing sends them into a spiral of anxiety and panic and overwhelm and it's just too hard whereas maybe for child b they're really really worried about being away from home because there's challenge going on at home and they're worried that if they're not there to keep things safe to keep an eye on things to look after siblings or a parent or a carer or what have you that that's a concern for them and then maybe there's child c who has got mental health concern perhaps they've got obsessive compulsive disorder and this makes getting to and into school very very challenging because they've got obsessions and compulsions that are driving them to do other things and taking their focus away from the school day there's like so many different things that could be underlying this and yeah could probably list a hundred different reasons so many different things but the point is if we don't know what the problem is if we don't know what is stopping this child from making it into school from thriving at school from enjoying school from being able to go there do that and and enjoy it and love it if we don't know the why for them then it's really hard for us to focus on the how to help so first we've got to find ways to work out the why and that can be a whole another video a whole another guide if you find that helpful do comment if you've got ideas on that do comment but just my first point here before we think about how do we help we've got to define what are we trying to help why is this child finding it hard