Section 73 of Final Report of the Advisory Committee on Human Radiation Experiments. Contemporary Projects. Chapter 15. Part 2. Issues Contributing to the Overall Ratings. In this section we examine the kinds of problems that troubled reviewers in the documents from the forty proposals that received ratings of three, four or five. These problems fell into three categories. One, factors likely to affect the adequacy of potential subjects' understanding of the research other than questions of competence. Two, factors likely to affect the voluntariness of potential subjects' decisions about participation. And three, approaches to the inclusion of subjects with limited or questionable decision-making capacity. Factors likely to affect understanding. Reviewers were likely to give a three, four or five to proposals whose consent forms did a poor job of describing either what potential subjects stand to gain or what they stand to lose by participating in research. We looked carefully at how the consent forms presented the purpose of the study, its potential for direct benefits to the subject, the distinction between direct benefits and benefits to medical science, and alternatives to participation. How well consent forms communicated the realities of what it would be like to participate in the proposed research, including the likely impact on quality of life, also came under scrutiny. We were troubled, for example, by consent forms that, when compared with the information provided in the grant proposal or other research documents, appeared to overstate the therapeutic potential of the research, either explicitly or indirectly. This issue was of particular concern to the committee when the subjects being recruited were patients with poor prognoses. For example, one study which was presented as primarily a toxicity study in the accompanying research documents, was cast differently in the consent form. One objective is to find out how well patients respond to treatment. If treatment works in your case, it may shrink your tumor or cause it to temporarily disappear, and or prolong your life and or improve the quality of your life. Another objective of this study is to find out what kind of side effects this treatment causes and how often they occur. There was also significant concern about the use of the word treatment in consent forms for pharmacological studies. Phase one studies are designed to establish the maximum tolerated dose, MTD, for new chemotherapeutic agents and radiation regimens, which are then subjected to limited phase two and then more extensive phase three clinical trials to determine therapeutic effectiveness. Although some phase one studies contain elements of phase two research and can appropriately be characterized as holding out at least a remote prospect of benefit to the subject, for some phase one studies even the suggestion that subjects might benefit is inappropriate. Reviewers were influenced in their overall assessments by inadequate descriptions of the physical risks of participating in the research. Reviewers were concerned, for example, when consent forms did not discuss the risks potential subjects faced in being removed from their standard treatments to be placed on an experimental protocol. In one study patient subjects were taken off cardiac medication in order to participate in a diagnostic study that offered no direct benefit to them. Any risks involved in the removal from this cardiac medication were not addressed in the consent form. The advisory committee also identified consent forms in which the possible lethality of drug treatments and radiation exposures were not adequately discussed. This occurred in contexts where patient subjects generally faced far greater risks from their underlying illnesses, but nevertheless we felt that the consent forms should have been more forthcoming. A number of projects that involved combination drug treatments, for example, did not provide the potential subject with an estimate of the possibilities of death or major toxicity from a combination of drugs. One study involved a combination chemotherapy consisting of twelve different drugs, but did not address the uncertainty of the risk resulting from this new and investigational combination. Although the hazards and side effects for each drug were described individually, there was no discussion of overall risks and harms. Even where consent forms described the risks of the research, there was often little mention of how participation would affect the subject's ability to function in daily life, or how ill subjects might be made to feel during the course of the research. This omission was of particular concern to us when the implications for quality of life were markedly different depending upon whether a person decided to participate in the research or accept standard medical management, such as when standard management included only palliative care or watchful waiting. In one end stage cancer study, for example, the consent form stated only that there may be other general complications which may occur from combinations of chemotherapy drugs, including weight loss and loss of energy. The advisory committee was troubled that in such studies patient subjects might not understand that although the research protocol might offer a chance to extend life, the time gained might be compromised by additional limitations in the quality of life resulting from participation in the study. Reviewers also noted a number of problems in some consent forms for randomized clinical trials. For example, when some patient subjects were randomized to receive the standard treatment while others would undergo an experimental procedure, reviewers commented that physical risks associated with the standard treatment or procedure were sometimes not adequately addressed in the consent forms. In one study of the effectiveness of a new compound for the decontamination of people who had ingested a radioisotope, although the grant proposal indicated that subjects would be randomized to receive a placebo, this information was not included in the consent form. In fact, the consent form only vaguely discussed the experimental procedures. I, subject name, authorized physician name to administer decorporation therapy utilizing the drug name of drug. The committee recognizes the difficulties facing investigators in communicating to potential research subjects a complex set of experimental procedures, side effects, long-term risks, trade-offs relative to alternatives, and other relevant information. This task is not impossible, however. We reviewed documents from several complex research proposals that at the same time had excellent consent forms. For example, we reviewed documents from a proposal for a phase one study of experimental antibody therapy that involved a number of possible risks, imposed a number of inconveniences including restrictions on sexual activities and a week-long time commitment, and as a phase one study offered little prospect of direct benefit to the subjects. The consent form for this study addressed each of these issues in understandable language, briefly described how the monoclonal antibodies used in this research were derived, and explained that the U.S. Food and Drug Administration, FDA, permits experimental new forms of therapy to be tested in a limited number of patient subjects in phase one studies. This consent form presented enough useful information to enable potential subjects to make an informed decision about whether to participate in the research, and it was not overly optimistic about the prospect of direct benefit to the patient subject. Another complex, greater than minimal risk study with a good consent form involved an investigational radiation treatment, radio surgery, for patient subjects who had vascular disorders of the brain. The consent form for this study described the experimental procedures step by step with a very realistic picture of what participation would entail. Potential risks, possible benefits, and alternatives to participation for this experimental therapy were clearly presented. Moreover, information that was likely to discourage some patients from enrolling, the possibility that participation in this study might limit the effectiveness of similar types of radiotherapy for the patient in the future, was disclosed in the consent form. Factors likely to affect voluntariness As is discussed later in this chapter, the documents we reviewed often provided no basis on which to judge whether the participation of potential subjects was likely to be voluntary or not. In some cases, however, the information provided was sufficient to raise concerns. One was a neuroscience study that offered no prospect of medical benefit to potential subjects. Subjects were being recruited from among former cocaine addicts who were living in a residential treatment facility. Although compensation was not needed to reimburse subjects for travel expenses or loss of income, subjects were being offered one hundred dollars to participate. Reviewers were concerned that this cash payment might make it easier for those people struggling to break an addiction to get cocaine. Moreover, as part of the study, cocaine was injected into the body in order to measure brain uptake. Even if this procedure was not likely to have a physiologic effect upon the subjects, we were concerned that subjects may have been encouraged to participate because the research involved the injection of cocaine. We were also concerned about how their receiving cocaine as part of the research might affect the subjects' perceptions of themselves during the recovery process. By contrast, the following text from a consent form for employee subjects, colleagues of the investigators, who are smokers, illustrates exemplary handling of the voluntariness issue in a minimal risk study. The study, which involved no risk of physical harm to the subjects, was designed to measure environmental tobacco smoke. Your participation in these experiments is entirely voluntary and you are free to refuse to take part. You may also stop taking part at any time. Because you are a colleague here at Research Institution, we want to be especially clear on this point. We have approached you about the possibility of your volunteering for these experiments. Your refusal to participate or to continue will not be questioned by us nor will it or should it be further discussed with anyone else. Inclusion of subjects with limited decisional capacity Several issues revolve around how certain factors that influence a subject's decisional capacity may affect his or her ability to understand the implications of participating in research. There is, for example, considerable controversy over how to conduct research ethically in emergency medicine, when, because of the acute nature of the medical problem, the patient is temporarily incapacitated and no family members are available for consultation. The documents of one proposal raised some of these issues. In this example, five minutes were allotted to obtain consent from subjects who were recruited in the emergency room while their chest x-ray films were being processed. Under the stressful conditions of an emergency room and while experiencing chest pain, the decisional capacity of potential subjects was likely to be severely compromised. Reviewers expressed concern about the subject's ability in such a context to comprehend the study adequately and then make a voluntary decision about whether or not to participate. In another study, women in pre-term labor were recruited to participate in a study that involved collecting data about the infants born to these women. Although the proposal stipulates that no mother will be approached while under undue stress or in excessive pain, reviewers were nonetheless concerned about consent having been solicited during pre-term labor. The advisory committee also reviewed the documents of studies involving children and adults with questionable decision-making capacity, several of which raised serious ethical concerns. Sixteen of the studies included in the advisory committee's review involved children as research subjects. Eleven of these sixteen studies, according to federal regulations, should have had ascent forms as well as parental permission forms. The documents we received on each of these proposals all included parental permission forms. We received ascent forms for eight of the eleven proposals. The three studies for which we did not receive ascent forms all involved greater than minimal risk, one of which may not have offered any prospect of medical benefit to the children's subjects. This last study illustrates a major issue in the ethics of research involving children. Current regulations permit the use of children as subjects in research that offers no prospect of direct medical benefit to them when the research poses no more than minimal risk. Non-therapeutic research on children posing more than minimal risk is permitted under special circumstances. A central, unresolved question is whether the administration of tracer amounts of radioactive materials to children can properly be classified as a minimal risk intervention. Eight studies in the project sample sought to recruit adult subjects with questionable decision-making capacity. Six of the eight appeared not to offer potential medical benefit to the subjects, two of the six were epidemiologic studies. The committee's concerns focused primarily on the remaining four studies, all of which involved diagnostic imaging with cognitively impaired persons such as those with Alzheimer's disease. The imaging processes required that the subjects' movements be restricted, yet there was no discussion in the documents or consent forms of the implications for the subjects of these potentially anxiety-provoking conditions, nor was their discussion of the subjects' capacity to consent or evidence that appropriate surrogate decision makers had given permission for their participation. We were particularly troubled that two of these studies exposed subjects to greater than minimal risks. The question of whether or under what conditions adults with questionable decision-making capacity can be used as subjects of research that offers no prospect of benefit to them is unresolved in both research ethics and regulation. When such research puts potentially incompetent people at greater than minimal risk of harm, it is even more ethically problematic. Common Problems with the Documents We turn now to a discussion of issues that emerged often in the documents we reviewed, including documents that raised only minor concerns. Consent Form Language Although inappropriate reading level in a consent form was generally not sufficient in and of itself to result in ratings of three, four, or five, it was sufficient for a rating of two. A significant majority, nearly eighty percent of the proposals receiving a one, included consent forms that used a reading level appropriate for the study population. By contrast, the reading level was judged to be appropriate in no more than half of the remaining consent forms. Reviewers raised a number of issues that they felt may have contributed to problematic reading levels in the consent forms. One such issue pertains to the complexity of the research being proposed. We were disturbed to find that in their attempts to convey complexities to the subject, investigators often drafted consent forms that were too lengthy, highly technical, and generally unintelligible. Consider the following, for example. The purpose of this study is to obtain a map of brain cholineric receptors. This is done by administering intravenously small amounts of a radioactive substance that attaches to brain acetylcholine receptors, and then producing a map of these receptors using single photon emission-computed tomology, SPECT. Still, another consent form included language such as you will then be positioned in a recumbent position, and another possibility is poor regional function because of ongoing or intermittent ischemia at rest, resulting in anginal symptoms and global function that is worse than it can or should be. A number of consent forms included standard boilerplate language that was often in a smaller type and distinct from the rest of the document. The presentation of information in this manner may have given subjects the impression that this information was less important and easily skipped. Sometimes these sections contained the only discussion of such critical topics as alternatives to participation, cost to the subject, confidentiality, potential benefits of participation, and voluntariness of participation. The advisory committee found that intramural institutions often used a standard consent form that contained boilerplate language provided by their respective agencies. The following passage is an example of such language. It appeared in smaller type at the top of consent documents, clearly separated from the rest of the text. We invite you or your child to take part in a research study at named institution. It is important that you read and understand several general principles that apply to all who take part in our studies. A. Taking part in the study is entirely voluntary. B. Personal benefit may not result from taking part in the study, but knowledge may be gained that will benefit others. C. You may withdraw from the study at any time without penalty or loss of any benefits to which you are otherwise entitled. The nature of the study, the risks, inconveniences, discomforts, and other pertinent information about the study, are discussed below. You are urged to discuss any questions you have about this study with the staff members who explain it to you. Reliance on Disclosures Not Subject to IRB Review When patients are being approached to participate in research that has implications for the medical management of their illness, it is understandable and indeed desirable that patient subjects discuss the proposed research with their treating physician. The committee was disturbed, however, when consent forms indicated that the only presentation to potential subjects of key information about the research was to take place in such undocumented discussions. This suggests that it is difficult, if not impossible, for IRBs to judge whether potential subjects were being provided an adequate base of information on which to make an informed decision. There is no documentary record, either in the consent form or in the other materials submitted to the IRB, of what potential subjects have or will be told about key aspects of research participation. In some cases consent forms indicated that the subjects themselves were responsible for approaching physician investigators for explanations of the choices available and guidance on how to compare the experimental protocol to standard treatment. Consider the following example. Your, your child's, doctor can provide detailed information about your or your child's disease and the benefits and risks of the various options available.  In this instance it is unclear whether the phrase your doctor refers to the patient subject's personal physician, a physician who is a member of the research team, or a physician who is both. This passage as well as passages in several other consent forms suggests that conversations between subjects and doctors occurred after consent was given. Examples of this follow. Severe and sometimes deadly side effects have occurred when high doses of this drug have been given. You and your doctor will determine whether the benefits of such treatment outweigh the risk. And you will discuss the options with your physician and decide between surgical alternative or medical alternative. Subjects in these studies may have received information critical to their decision making process only after giving their consent to participate in the research and without the IRB knowing the content of that information. This is particularly troublesome because these statements comprise the only discussions of side effects and alternatives respectively in these consent forms. Other consent forms seem to rely on disclosures that had already taken place by the time potential subjects were approached to give their consent, and so could not be afforded IRB review. One such consent form began. The following is a summary of the information your doctors gave you when discussing this treatment with you. Please read it and ask any questions you may have. The summary that followed provided little specific detail. The committee was left to wonder whether the IRB was in a position to make a judgment about the adequacy of this prior disclosure. Voluntariness. If an informed consent is to be a meaningful act of decisional autonomy, it is essential not only that the consent be based on adequate understanding, but also that it be substantially free from coercive or manipulative influences. We found, however, that many proposal documents, including applications to IRBs, did not contain enough information to make a judgment about the likely voluntariness of the subject's consent decisions. For example, there was often insufficient or no information about who was soliciting a potential subject's consent and under what conditions. Often the only information in the documents reviewed that bore on issues of voluntariness was the inclusion in the consent forms of boilerplate language to the effect that participation was voluntary. In most cases the issue of voluntariness was simply ignored in proposal documents submitted to the IRBs and funding agencies, precluding us and presumably IRBs from making any judgments about the procedures employed to ensure voluntary decision-making. Scientific merit. A controversy has long existed over whether the role of IRBs includes evaluation of the scientific merit of the proposed research. Some argue that evaluation of scientific merit lies outside the scope of IRB review, while their opponents contend that it is impossible to do a proper assessment of the benefit-to-risk ratio without evaluating the potential contribution to science. Based on the documents we received, it was sometimes difficult to make judgments about scientific merit. In some cases reviewers felt that they could not establish from the documents available to them whether there was sufficient scientific merit to warrant the exposure of human subjects to risk or inconvenience. Psychosocial and Financial Risks. In research where psychosocial risks were clearly an issue, these risks were often inadequately addressed in proposal documents. A number of proposals that included neuropsychological batteries, for example, failed to discuss the potential anxieties that may result from participation in the study. The objective of one research project involved the inducement of sadness in the subject. Neither the consent form nor the research documents addressed the possibility that the sadness would not resolve itself quickly and that psychological counseling or other therapy might be necessary. Four studies reviewed by the advisory committee involved DNA screening to determine the subject's carrier status for a particular gene. None of the proposals for these studies addressed the potential psychosocial impact of learning about one's carrier status, including possible implications for other members of the subject's family or the potential for insurance discrimination. The availability of genetic counseling for these subjects was not mentioned in consent forms. Reviewers also were concerned that some proposals did not clearly explicate the types of tests that were included in what was referred to as chronic disease screening in the consent forms. This lack of specificity was particularly troubling for chronic disease screenings that included human immunodeficiency virus HIV testing. Although the anxieties and social risks of HIV testing were likely to be addressed on a separate HIV-specific consent form, any study that requires HIV screening as part of its eligibility criteria should make that clear to subjects so that those who do not wish to undergo HIV testing can decline participation. Another area that was sometimes inadequately described in both consent forms and research documents was the financial cost to the subject of participating in the research. Costs were often briefly addressed in the boilerplate section of the consent form, but usually no project-specific information about actual expenses was offered to the subject. Reviewers were concerned that subjects might not appreciate the real costs and the possibility that insurance companies would be very reluctant to cover them. This omission was particularly troubling in studies involving seriously ill-patient subjects who may be at risk of spending much of their assets on research interventions at the end of life. Justice in the Selection of Subjects Most research documents did not include specific information about the subject populations that would be involved in the protocol. Unless IRBs are receiving more information on this topic than that provided in the documents reviewed by the advisory committee, they are clearly ill-equipped to address the social policy goal of including women, minorities, and other groups in research. The racial and ethnic composition of the subject sample, for example, was specified in only one quarter of the proposals whose documents were reviewed by the committee. The only frequently mentioned reason for excluding a person from participation in research was pregnancy. Pregnant women were explicitly excluded in 58 percent of the studies, 73 of 125, and were explicitly included in only five percent, six of 125 of the proposals. Pregnancy tests were often included in the eligibility screening procedures for women who were willing to participate in research. The RP-RP sample also included 13 studies in which women who were not pregnant were expressly excluded from participation. There was no scientific reason to exclude women as subjects of research in any of these proposals. In two of these instances, women were excluded expressly because of the possibility that they might become pregnant. The committee's interpretation of the implications of these findings can be found in the discussion section at the end of the chapter. End of Section 73. Section 74 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. Contemporary Projects, Chapter 15, Part 3. Independent Review of Proposals. One member of the Advisory Committee, Jay Katz, served both as a reviewer for the RP-RP and independently reviewed 93 proposals. Katz's independent sample was drawn from the same pool of proposals from which the RP-RP sample was drawn. It included examples of both radiation and non-radiation research, and was based on the same sets of documents as RP-RP. Although there is considerable overlap between the proposals included in Katz's review and those in the RP-RP, the samples are not identical. Katz reviewed the first 93 proposals for which the committee received documents, while the RP-RP sample was drawn from the entire pool of proposals for which documents were received, in order to achieve adequate representation by funding agency and type of research. In addition, a few of the studies reviewed by Katz were eliminated from eligibility in the RP-RP, because they did not fall within the biomedical categories established by the committee. Katz's review complements and strengthens the findings of the research proposal review project, whereas the RP-RP sought to investigate several basic issues regarding the conduct of human subjects research, including balance of risk to potential benefit, justice in the selection of subjects, the involvement of people with diminished decisional capacity, and the consent process. Katz focused exclusively on informed consent. In doing so he asked himself two interrelated questions. One, what can be learned about the contemporary informed consent process? And, two, how adequately does the process protect the rights and interests of research subjects? Although Katz appreciated that there was more to the IRB process than could be ascertained from the protocols and consent forms submitted to the IRB, he felt that consent forms constituted written documentation, not only of what the subjects ultimately agreed to, but also what IRBs considered to be adequate written disclosure for purposes of consent. With respect to these signed informed consent forms, he echoed a fellow committee member's observation that if such forms are not clearly written or are otherwise flawed in significant ways, it is likely that the oral interactions were similarly flawed. Of the ninety-three proposals Katz reviewed, he identified forty-one that posed greater than minimal risks to the subjects, and therefore that also raised significant and complex informed consent issues. Of these forty-one proposals Katz found that eleven, twenty-six percent, raised no or only minor ethical concerns, and were analogous to those warranting a committee rating of one or two. Thirty protocols, however, raised ethical concerns about the informed consent process analogous to a committee rating of three, four, or five. Of the thirty protocols, seventy-four percent, that raised serious problems, Katz felt that ten were borderline, analogous to a committee rating of three, and twenty raised serious ethical concerns of the sort analogous to those warranting a rating of four or five in the RPRP. Katz detailed the results of his review of these twenty problematic proposals for the committee, and a summary of his findings specific to those proposals is presented here. Physician investigators In his review Katz was struck by evidence of the dedication physician investigators brought to their task. They were concerned, and so informed IRBs about current treatments that were inadequate in eradicating disease, or at least in prolonging life. Moreover, physician investigators emphasized the importance of finding cures and not merely temporary or prolonged remissions. Katz also noted that a number of the troublesome research proposals appeared to be part of an underlying grand scientific design to gain basic knowledge in such areas as cellular immunology or molecular biology, which might eventually lead to more clinical research about therapeutic effectiveness. The primary purpose of these studies was to advance knowledge for the sake of future patients, not to benefit present patients. As investigators declared war on cancer and other ills, they often employed highly toxic agents to treat patients whose prognosis was grave. In their scientific protocols, the use of such agents was justified by arguing that only such aggressive approaches would ultimately lead to cure, although often only for future patients rather than present patient subjects. Katz, like the full committee, was concerned that at the same time documents from these proposals were devoid of any discussion of the impact of the research on patient subjects' quality of life, particularly in situations of terminal illness. He speculated that in their ultimate quest for finding cures, physician investigators often paid more attention to increased longevity for present patient subjects than to the quality of remaining life. Patient subjects. To Katz, the ancient but questionable proposition that physicians and patients share an identity of interest in medical decision-making becomes even more questionable in research settings where physician investigators have dual allegiances to their subject patients and to their research objectives. As did those in the RPRP, Katz noted that consent forms for the troublesome proposals were often written in ways that made it difficult, if not impossible, for patient subjects to come to a meaningful decision as to whether they wished to participate in research. Thus patient subjects seemed obliged to fall back on uninformed trust, based on a belief that physician investigators will act only to ensure a patient subject's therapeutic benefit. Katz identified five specific problems with the informed consent process. One, unclear purpose. Two, incomplete information regarding the consequences of participation in randomized studies. Three, confusing or incomplete discussion of risks. Four, exaggerated benefits. And five, insufficiency of information in consent forms provided to IRBs. His concerns are elucidated below. Specific problems with the informed consent process. Unclarity about purpose. Katz found that the most striking element of the troublesome consent forms was the lack of a forthright and repeated acknowledgement that patient subjects were invited to participate in human experimentation. All too quickly the language shifted to treatment and therapy when the latter was not the purpose and was only at best a by-product of the research. Like the other reviewers in the RPRP, Katz was particularly concerned with Phase 1 trials. As documented in some of the protocols in his examination, patient subjects may suffer life-threatening toxicities that may, though rarely, kill them. Nevertheless, such studies are important for the subsequent clinical trials and more widespread use in an attempt to save lives in the future. Katz's examination of consent forms revealed that investigators often did not take sufficient care to apprise patient subjects of the purpose of Phase 1 studies. Although the dangers of the research are often mentioned, this information was often compromised when the treatment dimension of the research was emphasized. Katz concurred with a fellow committee member, who observed through his participation in the RPRP, perhaps the consent form should not repeatedly emphasize that it is treatment, but I believe that it is the way it is perceived by the researchers themselves. Katz pointed out that the controversy over when, if ever, Phase 1 trials are to be regarded as potentially therapeutic has not been satisfactorily resolved with respect to the question, what must patient subjects know? The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, when addressing Phase 1 trials, recommended that patients not be misled about the likelihood or remoteness of any therapeutic benefit they might derive from such participation. Katz's review of consent forms revealed that the Phase 1 purpose is often dismissed and the therapeutic benefits are highlighted. Thus he was concerned that patient subjects are likely to be confused about what is being asked of them. The Consequences of Participation in Randomized Studies A number of the troublesome proposals identified by Katz involved randomized clinical studies in which patient subjects were assigned to two different experimental regimens to assess their comparative merits. These two procedures were generally described adequately in the consent forms. Patient subjects, however, were generally not apprised of the already accumulated knowledge about possible therapeutic benefits to be derived from each regimen. Although protocols submitted to the IRB contained some, but often incomplete, information about the greater promise of one procedure over the other, patient subjects rarely received such information. In one protocol, for example, investigators clearly indicated that clinical experiences with the combined administration of chemotherapy and radiation had demonstrated its effectiveness against cancer. But since no scientific randomized clinical study had as yet been conducted, the investigators intended to submit half of the subjects to radiation alone. Consent forms provided no clues about what had already been learned from clinical experience and non-randomized trials. In another randomized trial, the research objective required that half of the patient subjects submit to a mild treatment regimen and the other half to a more intensive one. Katz noted that quality of life impairments imposed by random assignment to one research arm over the other were not addressed in the consent forms. The consent forms also failed to address the fact that more intensive treatment regimens went counter to the customary clinical practice of watching and waiting, as the often slowly progressive nature of the cancer's underinvestigation had led practitioners to recommend, in most cases, doing nothing or administering chemotherapy or radiation therapy only in low doses. Moreover, the risks inherent in both the mild and aggressive regimens were lumped together in the consent forms as if they were one and the same. The history of clinical experience with these particular cancers was also not discussed in the consent forms. Discussion of Risks The troublesome consent forms identified by Katz customarily listed an extremely detailed and separate discussion of all the risks of the drugs, surgery, and or radiation to be administered. Although he felt that federal regulations can be interpreted to require such detail, Katz, like the advisory committee as a whole, was concerned that such exhaustive treatment may serve only to overwhelm and numb patient subjects. Only rarely were the risks summarized or were risks of particular relevance to the research project highlighted. In almost none of the troublesome consent forms was there any comparative discussion of the impact on quality of life and toxic consequences of what investigators sometimes termed total therapy, or of the physical and financial hardships imposed by countless research tests, on the one hand, and of the less toxic therapeutic alternatives that promise less but at least provide greater comfort for remaining life on the other. For example, one study sought to explore the toxicity and efficacy of a new drug that may cause irreversible brain damage. That crucial piece of information, however, was not highlighted as a specific risk of the particular drug under investigation. Another research project was designed to treat a cancer with a highly toxic drug, which had an expected mortality of up to ten percent, when used in a dosage greater than customary, as was contemplated in this total therapy research project. This fact, however, was not mentioned in the consent form. Although the patient subjects had limited life expectancies, they probably would live longer than when a lethal drug toxicity would occur. Cats noted that another investigator simultaneously submitted the identical study to the same IRB, utilizing the same drug to combat the same disease, but with an exemplary protocol and consent form, which discussed the expected ten percent mortality rate without equivocation. Presentation of Benefits Like the RPRP reviewers, cats found that benefits were often exaggerated in the troublesome consent forms. One consent form, for example, stated, it is possible that the treatment, emphasis added, will cause the tumor to shrink or disappear or eliminate any symptoms and thus increase life expectancy. Although this statement conveys a promise of benefit to the patient subject, the protocol clearly indicates that any benefits would be fortuitous, since they were neither an aspect of the research objective nor supported by evidence so far accumulated. One consent form for a research project that was designed solely to establish the maximum tolerated dose of an intensive chemotherapy schedule stated, it is not possible to predict whether or not any personal benefit will result from the use of the treatment program. A possible benefit could be the achievement of a remission. There was, however, no therapeutic intent in this proposal. Physician investigators were interested only in learning if it could be used safely in a subsequent randomized clinical trial. The subjects, however, could easily be led to believe that there was a probable therapeutic benefit. Cats was particularly alarmed about the overstatement of benefits because patient subjects so desperately long for such benefits. Insufficiency of information provided to IRBs. In many cases cats found discrepancies between information provided in the protocol and that provided in the consent forms. This finding was not unlike that of the full advisory committee. Thus an important question must be posed and eventually answered. Why was information that was available to the IRBs not disclosed to patient subjects? According to the documents received it seemed that even IRBs were often inadequately apprised of crucial information. In some cases cats noted that proposals were deficient in explicating the available knowledge about standard treatments, therapeutic effectiveness, and the impact of experimental procedures on quality of life. Although research is often a voyage into the unknown, investigators do possess preliminary guiding data that must be transmitted to IRBs. Only then can IRBs accurately evaluate consent forms and make certain that patient subjects are provided with the necessary information in order to make decisions about participation. In one research project, for example, IRBs and in turn patients were insufficiently informed that the combination of radiation treatment and highly toxic chemotherapeutic agents used in the project exposed children to considerable risks that deserved careful scrutiny. The parents or guardians had two choices, to enroll their children in the study, or to opt for standard treatments of either radiation or chemotherapy alone, depending also on the location of the cancer, with or without one of the chemotherapeutic agents that had considerable carcinogenic potential within five years. This example highlighted another more general concern, that some patient subjects may become part of inflexible research protocols when considerable clinical experience suggests that a patient subject's medical condition may deserve an individualized treatment approach. Discussion We now turn to a consideration of the implications of the results of the RPRP as bolstered by Katz's review for our understanding of the current status of human subjects' protections. It should be re-emphasized that these results were based solely on an evaluation of the documents available to the committee. It is therefore possible that some of the research projects that raised concerns for us based on the documents we reviewed would, with the provision of additional information, be deemed unproblematic from a human subject's perspective. It is also possible that some of the research projects whose documents raised no concerns may nevertheless have inadequacies affecting the rights and interests of human subjects that we could not detect. There is no evidence in this review that research in which human subjects are exposed to radiation is any more ethically problematic than other kinds of research involving human subjects. In fact, our results suggest that human subject protections may be more effective in radiation research than elsewhere, perhaps because some radiation research is reviewed by a Radiation Safety Committee as well as an IRB. Because we failed to find any systematic differences between radiation research and non-radiation research in our review, our observations based on the RPRP results are directed at human subjects' research generally, not solely at radiation research. About forty percent of the research whose documents we reviewed appeared to pose no greater than minimal risk to participants. Most of these studies raised no concerns about ethics or only minor ones. Many studies that involved greater than minimal risks to subjects were similarly ethically unproblematic. Specifically, more than half of the greater than minimal risk studies reviewed raised no or only minor concerns about ethics. There are important lessons to be learned from these studies. It is possible to conduct complex research that puts subjects at greater than minimal risk of harm in an ethically acceptable fashion. It is possible to develop good consent forms for this kind of research. Not only is it possible, but it appears that this happens frequently. At the same time, our review suggests that there are significant deficiencies in some aspects of the current system for the protection of human subjects. We have evidence that the documents provided to IRBs often do not contain enough information about topics that are central to the ethics of research involving human subjects, such as voluntariness of participation, fairness in the selection of subjects, and scientific merit. Although we have already noted that IRBs do not necessarily rely solely on the documents in making their evaluations, clear, complete written documents are important. These documents form the core of the information upon which IRBs rely in protecting the rights and interests of human subjects. In some cases they are the only source of information available. These documents also provide a written record of the research-subject protection process for both administrative and historical purposes. In some cases the committee found that it was difficult to assess the scientific merit of a protocol based on the documentation provided. This is particularly problematic for proposals in which the IRB provides the only opportunity for peer review, as is sometimes the case for research that is not funded by the federal government. The committee also found evidence suggesting that in some studies women are being excluded from participation in research explicitly or presumably because of the possibility that they might become pregnant during the course of the study. This finding is disturbing in light of the fact that much of this research was undertaken after a national policy had been instituted advocating the inclusion of women in research, and a general rejection of the mere possibility of pregnancy as a justifiable reason for not permitting women to become research subjects. The conditions under which pregnant women ought to be included as research subjects remain controversial, that pregnant women are frequently excluded from research was clearly evidenced in the RPRP. This occurred in more than half the studies in our review. Some of the committee's most serious concerns focus on informed consent. The results of the RPRP, as well as of Katz's review, suggest that some consent forms currently in use are flawed in morally significant respects, not merely because they are difficult to read, but because they are uninformative or even misleading. These are consent forms that have been approved by an IRB, and still they are problematic to the point where committee reviewers viewed them as raising serious ethical issues. Most of these concerns centered on research involving patient subjects with poor prognoses, people who are particularly vulnerable to confusion about the relationship of research to treatment. The consent forms to be used with such patient subjects sometimes appeared to suggest a greater prospect of benefit than the research as described in the documents we reviewed warranted. In a few phase one studies, any intimation that subjects would benefit appeared questionable. At the same time the disadvantages of participation, particularly as they would affect quality of life, were sometimes inadequately described or not presented at all. The committee recognizes that the consent form is only a document and is never to be confused with the entire process of soliciting informed consent, which includes far more than the form itself. It is possible that in some of these cases potential patient subjects were provided more balanced and straightforward information in discussions with investigators or their own physicians. At the same time, however, the consent form as approved by the IRB is a powerful symbol of what the system considers an adequate disclosure. Moreover, this may convey to investigators that meeting ethical obligations to potential subjects requires the investigators to say nothing different and nothing more than what is approved in the consent form. Our review also raises serious concerns about some research involving children and adults with questionable decision-making capacity. Although we looked at documents from only 125 proposals, we found examples of three controversial unresolved issues in the ethics of research. Research with patients in the midst of a potential medical emergency, research involving children that may offer them no prospect of direct benefit but that may put them at greater than minimal risk, depending on how minimal risk is understood, and research on adults with questionable decision-making capacity that offers them no benefit but that involves unpleasant procedures and exposes them to greater than minimal risk of harm. All told, the documents of almost half the studies reviewed by the committee that involved greater than minimal risk raised serious or moderate concerns. Cats, who focused exclusively on the informed consent process, had serious concerns about fifty percent of the greater than minimal risk proposals he evaluated. These are findings that cannot be ignored. At the same time, our review provides evidence that research involving human subjects, even complex research, can and often is being conducted in an ethically responsible manner. The challenge is to identify what needs to be changed to ensure that all research involving human subjects is conducted in accord with the highest ethical standards. End of Section 74, Recording by Maria Casper. Section 75, a 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. Section 75, Contemporary Projects, Chapter 16, Part 1. Chapter 16, Subject Interview Study. In reporting to the American people what we have learned about the current status of human subjects research, the committee wanted to incorporate the voices and experiences of subjects themselves. What is it like to be a subject in biomedical research today? Why do people become research subjects? And what does participating in research mean to them? To provide answers to these questions, the advisory committee conducted the subject interview study, SIS, a descriptive study in which both patients who were research subjects and patients who were not research subjects were interviewed to determine whether they believe that they were participants in medical research. Their general attitudes and beliefs about medical research and, if applicable, why they did or did not decide to participate in research. The committee would have liked to have heard not only from patient subjects but also from the many healthy volunteers who are critical to the success of biomedical research. Unfortunately, time constraints made this impossible. Clinical research, research involving patients, does account for a large portion of contemporary medical research involving human subjects, however, and it was toward this enterprise that the SIS was directed. In this chapter, we report what patients and patient subjects told us about research and what we learned about their experiences. We begin by describing the methodology of the SIS, how the patients were selected and how they were interviewed. Next, we report the results of these interviews, as well as the results of our review of the records of the patients to whom we talk. We close with a discussion of the limitations and implications of the SIS. Methodology. The SIS included almost 1900 patients at medical institutions across the country. To determine whether the experiences people had with radiation research were any different from those people who had non-radiation research, we interviewed patients in medical oncology, radiation oncology, and cardiology clinics. All of these patients participated in a brief survey, five to ten minutes. 103 of these patients, all of whom reported in the brief survey that they were research participants also completed longer, roughly 45 minutes, in-depth interviews designed to give patients an opportunity to elaborate on their perceptions of research and their personal research experiences. Advisory committee staff and consultants took primary responsibility for designing the SIS, recruiting institutions to participate in the study, conducting some of the interviews, and analyzing the data. Research Triangle Institute, a non-profit organization, was hired to perform several tasks, including conducting focus groups, piloting the interview instruments, conducting the majority of interviews, and performing most of the data entry. Selection of institutions. Five areas of the country were selected as sites for the SIS. Ann Arbor, Baltimore, Washington, Dallas, San Antonio, Raleigh, Durham, and Seattle, Tacoma. These sites were selected because they include institutions that receive some of the highest amounts of federal dollars for human subjects research because we're trying to balance our sample with respect to geographic region, rural, urban settings, and expected ethnic mix. At each of these five sites, a university hospital, a VA hospital, and a community hospital were selected. If other federal government or military hospitals were present at a site, the most highly funded of these institutions were included. A total of 19 institutions were selected as presented in table one. Interviews were conducted at 16 of the 19 institutions selected. At the University of Washington Health Services Center and the Seattle Veterans Affairs, the institutional review board, IRB, process could not be completed within the time constraints of the SIS. Baylor University Medical Center declined to participate in the study. Table one. Institution selected for the subject interview study. Ann Arbor. Ann Arbor Veterans Affairs Medical Center. St. Joseph's Hospital. University of Michigan Medical Center. Baltimore, Washington. Baltimore Veterans Affairs Medical Center. Clinical Center of the National Institutes of Health. Greater Baltimore Medical Center. The Johns Hopkins Hospital. Walter Reed Army Medical Center. Dallas San Antonio. Baylor University Medical Center. Dallas Veterans Affairs Medical Center. Parkland Memorial Hospital and the University of Texas Southwestern Medical Center at Dallas. Wolford Hall Air Force Medical Center. Durham Raleigh. Duke University Medical Center. Durham Veterans Affairs Medical Center. Rex Hospital. Seattle Tacoma. Madigan Army Medical Center. Seattle Veterans Affairs Medical Center. Swedish Hospital. University of Washington Health Services Center. Interviews were not conducted at the following institutions. Baylor University Medical Center. Seattle Veterans Affairs Medical Center. University of Washington Health Services Center. Recruitment of patients. At each of the participating institutions, patients were recruited from the waiting rooms of three outpatient departments. Medical oncology, radiation oncology, and cardiology. On the days that patients were seen in each of the departments, a clinic staff member informed patients arriving in the clinic that a study was being conducted to examine attitudes and beliefs about participation in medical research. The staff member also asked patients if they were willing to have a study interviewer approach them in the waiting room to see if they were willing to be interviewed. Interviewers approached a systematic sample of these patients and following a brief description of the SIS asked individuals to participate. Each patient who agreed to participate in the brief survey completed a written consent form that authorized the SIS staff to consult one or more of the following sources to ascertain whether the patient was or had been a participant in a research project. Doctors, investigators, research nurses, a research office, a research database, and their medical research records. The survey, composed mostly of multiple choice questions, was designed to take roughly five to ten minutes to administer. Patients completing the brief survey received five dollars for their time and effort devoted to the study. All patients who indicated in the brief survey that they believed they were medical research participants were asked if they were willing to participate in an in-depth interview, roughly 45 minutes. These interviews raised many of the topics from the brief survey. A sample of those who agreed to this further participation were contacted to arrange for an interview at a time and place convenient for them. Patients completing the in-depth interview received 25 dollars to compensate them for their time and effort devoted to the study, as well as to pay for any expenses related to participation in the study, such as transportation and parking. A target of 150 brief surveys, 50 each in medical oncology, radiation oncology, and cardiology, was set for each institution. The target of 100 total in-depth interviews was set for patients selected from all institutions. Both the brief survey instrument and the in-depth interview guide appear in a supplemental volume to this report. Electronic files containing the final data from the brief survey and transcripts from the in-depth survey are maintained along with the records of the advisory committee. Data collection and analysis. Brief survey. The brief survey instrument was refined based upon focus groups of patients conducted at two institutions not participating in the SIS, the University of North Carolina Chapel Hill, and Georgetown University. The instrument was then further refined based upon pilot testing at these same institutions. The instrument consisted predominantly of questions with multiple choice answers addressing, one, general attitudes toward medical research, two, any perceived differences and understanding among the following terms, medical research, medical study, clinical trial, clinical investigation, and medical experiment. Three, beliefs about research participation. Four, reasons for either participating in research or not participating in research when applicable. And five, demographic and other background information such as race, sex, age, and employment, insurance status. All survey forms were labeled with an identification number for each patient rather than with patients' names. Data were entered into a computerized database and analyzed using standard statistical methods. In-depth interview. An in-depth interview guide was developed based on the focus groups and pilot testing at the University of North Carolina Chapel Hill and Georgetown University. The in-depth interview contained open-ended questions that allowed participants to speak more extensively about the issues addressed in the brief survey. For example, patients were asked to describe their attitudes about research generally, their own experience as research participants, how they arrived at their decision to participate, and the informed consent process for their particular project. All of the interviews were audio taped and transcribed. All cassette tapes and transcripts were labeled with an identification number for each patient and never with patients' names. All transcripts were read in their entirety by advisory committee staff members and then data were coded and analyzed using text analysis software. Determination of research participation. To assess how well patients' reports of their participation in research match their documented enrollment in research projects at the participating institutions, a mechanism for determining research participation was developed for each institution. In each instance, we sought documentation of participation and research from sources such as patients' medical or research records. This information was supplemented by information from investigators and research nurses. A second level of review was conducted in those cases in which there was an apparent discrepancy between a patient's own description of having been or not having been a research subject, and the documents or other sources of this information. A physician or a research nurse on the advisory committee staff reviewed the patient's interview, the patient's medical and research records, institutional databases, and other sources of information at the local institution for evidence that could either resolve or verify the discrepancy. Expert panel assessments of the research projects. To identify some of the basic characteristics of the research projects in which the patients we interviewed were or had been participating, we convened an expert panel and asked this panel to make some preliminary judgments based on the information provided in the consent forms of these research projects. The panel consisted of eight physicians, specialists in oncology, radiation oncology, cardiology, nuclear medicine, and radiology, as well as general internists. We attempted to secure a copy of an unsigned consent form for every research project in which a respondent in the SIS was a documented participant and that had been conducted at one of the study institutions. Although 336 consent forms were requested, only 236 were received in time to be reviewed by the expert panel. Each consent form received was reviewed by the expert panel, which meant for one day. After agreeing how the forms would be evaluated, the panel broke into four teams, each consisting of two physicians, one who had content area expertise in the project being reviewed, and another who did not. If a team could not reach consensus on the evaluation of a particular consent form, it was brought to the larger group for review. But consent form was received after this meeting of the panel, it was sent to the panelists for review. The expert panel characterized the research projects on three dimensions, type of research, therapeutic, diagnostic, or other. Degree of sickness of the population expressed as a high burden for those with diseases such as AIDS, a medium burden for those with conditions such as hypertension, or a low burden for those who generally were healthy, and incremental risk assumed by those who participated in the project compared with those who were not participating in the research project measured as minimal or more than minimal incremental risk. Results. In this section we present the results of the SIS. We begin with a description of the demographic characteristics of the patients we interviewed, as well as the basic characteristics of the research projects in which some of these patients were or had been participating. We then review what we learned about patients general attitudes toward and beliefs about research and their understanding of some of the terms commonly used to describe research to potential subjects. This is followed by our results concerning patients' perceptions of whether they are or are not participants in research, and the extent to which we are able to compare these perceptions with documents and other sources. We then discuss what patients said about the distinctions between research and treatment, and the reasons for deciding to participate. We also describe the characteristics of patients who reported that they declined to be research participants. Our discussion of results closes with what we learned from the SIS about the consent process and issues of voluntariness of participating in research. Demographic information. Brief Survey. A total of 1,882 patients completed the brief survey. The overall response rate was 95 percent. Patients predominantly were Caucasian, 80 percent, more than 60 years old, 53 percent, and male, 59 percent. Other relevant demographic features are found in table two. In-depth Interview. A total of 103 patients representing 14 of the 16 institutions included in the overall study sample were interviewed. This sample also was predominantly Caucasian, 74 percent, and male, 54 percent. See table two. Due to technical or administrative difficulties with four interviews, only 99 transcripts were available for analysis. Characteristics of the research projects. The characteristics of the projects in which patients participated are described in table three. The expert panel characterized the disease burden associated with the projects reviewed as low, 11 percent, medium, 38 percent, and high, 51 percent. Approximately half, 48 percent involved minimal incremental risk from research. Table two. Demographic characteristics of SIS patients. The percentage is given will be first for the brief survey and then for the in-depth interview. Again, the brief survey included 1,882 individuals. The in-depth interview was conducted with 103 individuals. 6. Male. 58.7 percent. 54 percent. Female. 41.3 percent. 46 percent. Age category. Under 30. 3.6 percent. 5 percent. 30 to 59. 43.3 percent. 53 percent. Over 59. 53.1 percent. 42 percent. Race ethnicity. African American. 16.3 percent. 23 percent. Caucasian, 79.7 percent. 74 percent. Latino, 3.9 percent. 2 percent. Other, 2.9 percent. 1 percent. Education. Less than high school. 21.5 percent. 9 percent. High school graduate plus those with additional schooling. 53.7 percent. 52 percent. College graduate plus those with additional schooling. 24.9 percent. 39 percent. Annual household income. Greater than $75,000. 10.9 percent. 21 percent. 50,000 to 74,999. 14.4 percent. 15 percent. 25,000 to 49,999 dollars. 28.7 percent. 25 percent. Less than 25,000 dollars. 41 percent. 34 percent. Not reported. 5.1 percent. 5 percent. Insurance. Private. 87.2 percent. 65 percent. Public. 46.4 percent. 36 percent. Veterans administration. 26.6 percent. 20 percent. Not reported. 1.4 percent. 12 percent. Type of institution. Community. 37.7 percent. 34 percent. VA medical. 19.7 percent. 17 percent. University. 28.5 percent. 17 percent. Government. Military. 24.1 percent. 32 percent. Table three. Characteristics of research projects. The first percentage will be the patients report. The patients report refers to the patient's understanding of the type of research in which they were participating. The second percentage is the expert panel report, and that refers to the expert panel's assessment of the type of research in which the patient was participating. For the first, the total number of patients reports was 476. Because of time constraints, the remaining consent forms were not reviewed in the expert panel. There were only 236 of these reports. The type of research reported. Therapeutic. 65 percent. 69 percent. Diagnostic. 16 percent. 18 percent. Other. 14 percent. 12 percent. Did not know. 3 percent. Not available. Missing or unreported. 2 percent. And 1 percent. And of section 75. Section 76 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 Julian Henry. Final report of the advisory committee on human radiation experiments. Contemporary projects, Chapter 16, Part 2. General attitudes toward and beliefs about biomedical research. Brief survey. In the brief survey, patients were asked a series of questions concerning their attitudes toward and beliefs about medical research. Almost all of the patients had positive impressions of medical research. Specifically, 52 percent reported a very favorable attitude toward research and 37 percent a somewhat favorable attitude. Only 5 percent of patients described themselves as having an unfavorable attitude. Controlling for multiple factors, the characteristics associated with more favorable general attitudes toward research included being older, age greater than 60, being male, being a patient in radiation oncology rather than cardiology and having reported currently being or having been a participant in research. More than two thirds of the patients reported that they believed medical research usually or always advances science. More than 80 percent of the patients agreed that medical research does not involve unreasonable risks, 86 percent. Nevertheless, some patients, 9 percent believed that research usually or always poses unreasonable risks to people. Controlling for multiple factors, the characteristics associated with holding this belief included being younger, being African American, not having a college education, being in fair or poor general health, and not having any experience as a research participant. 7 percent of patients believed that participants in medical research are usually or always pressured into participating. Patients more likely to believe that people are pressured into research were African American and had an annual income of less than 25,000 dollars. 37 percent of patients believed that patients who participate in medical research are usually or always better off medically than similar patients who are not in medical research. Patients with a more positive view about research tended to be older have incomes of less than 50,000 dollars a year and have had some experience as a research participant. In-depth interview. In the in-depth interviews, patients general attitudes about research often seem to be shaped by what their own research experiences had been, and patients generally had very positive things to say about their own experiences. Typically, they believed that the projects in which they were or had been participants had been explained thoroughly, that they had been treated kindly, and that they had received at least as much benefit as could have been expected. Moreover, the more experience people had with research, the more positive was their attitude. In addition, a few patients admitted that they had held a rather negative impression of research until they themselves had participated at which time their impression changed. One respondent said, I didn't know what to expect. In the beginning, I was worried, you know. I was a little upset, a little frightened and everything. Once I got there, I found that the people were very nice, very professional, and they care about their patients. You think that you are going to be a number that they just may be cold and calculating. They'll just be thinking about just the data itself, and you are just a number or something. But once I got there, I found that the doctors and nurses and everybody are very concerned about the individual, and you find that out because they take the time to know your name. These findings are consistent with those from the brief survey in which patients who currently were or once had been research participants had significantly more positive attitudes about research than those who had never participated. When asked for their attitudes and beliefs about medical research generally, rather than about their own experiences, patients again had very positive things to say. Research was thought of as a promising endeavour, something that would advance knowledge and help other people. Research is the only way advancement is made in the medical field particularly. It's got to be done at some point in time on human beings, and there are people who are alive today because of the people who did research projects. Another respondent strongly endorsed research activities. Overall I have to say clinical trials, medical experiments are the only way we're going to find any type of results, because you can practice on guinea pigs, monkeys or whatever, but the only way you're going to find out if any of these drugs are going to work is you're going to have to do it on a human being. While patients are articulated the necessity of conducting research, a few reiterated the importance of looking out for the interests of the human participants. I think that research is awfully important in all fields, and the more it involves human life, the more guarded one has to be about it. Terminology, brief survey. In the brief survey patients were asked to compare the term medical research with one of four alternative terms, clinical trial, clinical investigation, medical study or medical experiment. The term medical experiment evoked the most striking and negative associations. It was the only term to be evaluated as worse than the term medical research on all of the dimensions considered. Specifically patients who were asked to compare medical experiments with medical research reported that patients in medical experiments were more likely to get unproven treatments and be at greater risk than patients in medical research, and also that they were less likely to do better medically. By comparison, patients thought those in medical research were more likely to those in either clinical investigations or clinical trials to get unproven treatments and to be at greater risk, but they were more likely to do better medically. The term medical study got better ratings than the term medical research in every respect. Medical studies were viewed as less risky, as less likely to involve unproven treatments, and as offering a greater chance at medical benefit. In-depth interview. Distinctions in meaning among different terms for biomedical research also emerged from the in-depth interview. Elaborating on the findings of the brief survey, the terms experiment and experimental for the vast majority of participants meant that something was unproven, untested, or in the first stage of testing, and was thereby riskier and perhaps scary. Some patients said they would become a participant in an experiment, only if they were terminally ill. A few participants described quite explicit images of what experiments involved. I envision all kinds of weird things done to the body, and I assume that's not true, but also I envision a medical experiment may be done in a laboratory sealed up somewhere where no one even knows what's going on. Another respondent said, medical experiment almost sounds like Frankenstein to me. When asked to explain the term experiment, patients often invoked the term guinea pig to convey the sentiment of being the victim of an experiment. For example, one respondent, when asked to define the term medical experiment, said, that's where you get down to the human guinea pig, where they might be injecting medication or whatever they want to inject in someone, and watching them for a reaction. In comparison with the term experiment, clinical trial and clinical investigation were not such evocative terms. Some patients gave hesitant or stumbling definitions, or said they were not familiar with these terms. On the other hand, some patients did attach meaning to these terms, defining them as endeavours that were at an intermediate stage of inquiry, where researchers already know something about the topic, and they are now trying the next step. Patients were most likely to consider study, a benign endeavour akin to studying something in school. Study brings to my mind more of using documentation for analysis. With a study, you're looking at records. You look at past histories and so forth. It is mostly paperwork, documents, or the books and things. Of the four terms offered, patients usually said they would prefer to be in a study. It was reported to be the least harmful because it was believed to be the least invasive. In comparison to experiments which many patients believed involved trying things out on animals and or humans, studies they felt usually entailed gathering information and reviewing paperwork. Personal experience with research. Brief survey. 30% 570 of the 1,882 patients interviewed reported that they were or had been participants in research, C-Table 4. We were able to review records or consult other sources for 541 of these 570 cases By these reviews, we were able to confirm research participation in 302 of 541 cases, 56%. In another 203 of the 541 cases, 38%, we were unable to find documentation to suggest whether or not the patient was participating or had participated in research. In the remaining 36 cases, the reviews by health professionals on the advisory committee staff concluded that these patients were probably in error and that they were not indeed research participants. In summary, 16% 302 of 1,882 of the total sample consistent with their reports were former or current research participants. Also assuming that most of the patients for whom research participation could not be verified but consistent with their own reports were probably truly former or current participants. 11% or 203 of 1,882. Then a total of 27% of the brief survey respondents were former or current research participants. By contrast, 2% of the total sample, 36% of 1,882, were likely incorrect in their perception of themselves as being participants in research. Table 4. Personal experience with participation in research. Results of the record review. Note, the numbers in this table should be interpreted in the context of the explanation and limitations presented in the text, pages 10 to 12 and 21 to 24. End note. Result of record review. In research, subjects who reported they were in research, n equals 570, 53% 302. Subjects who said they were not in research, n equals 1,223, 5% 69. Couldn't tell. Subjects who reported they were in research, 36% 203. Subjects who said they were not in research, 2% 23. Probably not in research. Subjects who reported they were in research, 6% 36. Subjects who said they were not in research, 88% 1,080. No record review. Subjects who reported they were in research, 5% 29. Subjects who said they were not in research, 4% 51. End of table. 65% 1,223 of 1,882 of the patients interviewed reported that they were not and never had been participants in research. We were able to review records or consult other sources for 1,172 of these cases. In 23 of the cases, relevant records were unavailable to confirm participation. In our review of records and other sources, we did not find evidence of research participation for 1,080 of 1,149 patients. In 69 of these 1,149 cases, however, advisory committee health professional staff was able to confirm patient's participation in research. In 61 of these 69 cases, the preliminary evidence for participation had included an informed consent form signed by the patient for enrolment in the research project. In summary then, 60% of the total sample 1,080 of a total of 1,882 appear never to have been research participants in the sense that there is no evidence to the contrary and in another 1% of the sample, 23 out of 1,882, it is unclear. By contrast, 4% 69 of 1,882 of the total sample were apparently incorrect in believing they had never been participants in research. Although the committee could not return to the 69 subjects to determine whether the apparent discrepancy was due to true lack of awareness or perhaps to other factors like confusion, misunderstanding of the question or poor memory, we did attempt to take a closer look at these cases. The 69 patients came from all five geographic sites sampled in the SIS and were receiving care at every type of institution participating in the study, that is university hospitals, government or military hospitals, veterans affairs, medical centers and community hospitals. These patients were interviewed in radiation oncology, medical oncology and cardiology clinics. Their ages ranged from 21 to 89 years of age, 30 were women and 39 were men and the majority 53 were white, 12 were African American and four were of other ethnicities. Their educational background ranged from less than eighth grade to those with graduate or professional degrees. The records of these 69 patients who reported that they were not in research but for whom evidence of research participation was found were subjected to extensive review and analysis by advisory committee health professional staff. According to this review about half of these patients had been enrolled in research during the previous year. The consent forms of 42 of the studies in which these patients were enrolled had been included in the sample of consent forms reviewed by our expert panel. According to the panel the disease burden for those recruited for these 42 studies ranged from low five studies to high 18 studies with the remainder being medium 19 studies. Most of these studies involved the evaluation of treatment 23 studies while some were diagnostic 13 or other types of studies five. Finally of these 42 studies 25 were determined by our experts as posing minimal incremental risk to subjects and 17 as posing more than minimal incremental risk. In-depth interview. Patients completing the brief survey were recruited for the in-depth interview if they reported that they currently were or once had been participants in research. Through the review process described above however research participation could not be verified for nine of the 99 in-depth interview patients nor did the transcripts of these nine patients suggest that they were research participants. Two of these nine patients told stories about research participation that were confusing or unclear. Another seven of the nine seemed to believe that anything new or unknown or in a few instances any tests were research. One such respondent with a rare medical condition without a known efficacious treatment described the interventions she received and said everything is experimental they don't know how to cure it. These nine transcripts were excluded from further analysis. Distinctions between research and medical care. While the brief survey did not address distinctions between medical treatment and research this issue arose during the in-depth interview. Here patients descriptions of their research experiences often included descriptions of their physical conditions their own health care providers or the hospitals at which their research projects were conducted. Research experiences particularly for those patients who reported being in research evaluating potential treatments were inextricably interwoven with their medical care experiences. One respondent described her research experience as a means of treating what I have. Another respondent when asked what she disliked about the project in which she was a participant replied nothing other than the fact that nobody likes to be sick and nobody likes to go to doctors. While patients if asked were quite able to identify which procedures tests and staff were associated with their research they did not themselves readily make distinctions between research and medical treatment. Particularly for patients with serious medical diagnosis research often was viewed as one of the treatment options for their medical conditions. Not surprisingly then some participants evaluated their research experience in terms of whether they believed it would provide them with clinical benefit. One respondent noted I see results that indicate that the chemotherapy that I'm taking is working and therefore that is adequate enough to satisfy me. Despite the tendency for some patients to fuse discussions of research and treatment some clearly differentiated the two. This was especially true for those who reported that they were in diagnostic epidemiologic or survey research. End of section 76


Hey guys, back from PAX. This video is like two weeks late, I apologize. Anyways, I just sort of wanted to talk about, I'm probably going to do just two or three videos about PAX. Was this fun? It was a fun time. There was a lot of VR, a lot of VR comparison to previous years. One of the biggest VR lines was Resident Evil 7, which was, oh, it's not a game, it's not a demo. It was literally just you sitting in a chair being scared by something. I might put up the video for that in a little while, but the one game that I really wanted to talk about with you guys is a game called Blasters of the Universe and this is a game that was made by a company from Toronto and at first they were probably one of the quieter VR booths in the indie area, but then as I went back, it was their Friday, Saturday, Sunday, I kept going back there every day and on Sunday the line was, they had completely filled up their line for the whole day and that was at two and which was awesome because those guys really worked hard to make that game. They kept on really letting people try it, they kept on talking to people. It was one of the funnest games I played because of this. Now this video here, you'll see that it's actually a very, very simple game. It's a shooter. You're standing in one place. Not really, okay, I'll take that back. You're not standing in one place.   I lost track of how many times I actually tried this game. It was so fun. I had such a good time playing it and if you guys have a VR, or a headset, an HTC, or a Oculus Rift, it's all, I think it's an early access right now. Get it. If I had the money, I would buy a headset and do that too because that's, it was honestly really fun. I got so into it that I almost took out one of the developers. Anyways, that's more of someone I want to talk about. I also got a mug. It's this checkpoint on it. I had to get a new mug. I was going to think about getting a shirt. I got one that I'll probably wear in the next video but what I thought was really odd was how they didn't have a lot of shirts to choose from. See, this is a shirt I bought when I first went to PAX nine years ago and I thought, you know, if I go 10 times on the 10th time, I'll get a shirt, another shirt. So I'm really hoping they have more than four. They had four and then the PAX Prime 2016. Either way, fun time. Swag was very small but the other video I'm going to do is I'm actually going to be giving away a few things that I got while at PAX. So make sure to check in for that video. See you guys later.