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Complex calculations: ethical issues in involving at-risk healthy individuals in dementia research Robin Pierce J Med Ethics 2010 36: 553-557 originally published online July 31, 2010

doi: 10.1136/jme.2010.036335

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Research ethics

Complex calculations: ethical issues in involving at-risk healthy individuals in dementia research Robin Pierce Correspondence to Dr Robin Pierce, University of Oxford, Wellcome Centre for Neuroethics, 16e17 St Ebbe’s Street, Suite 8, Littlegate House, Oxford OX1 1PT, UK; [email protected] Received 1 March 2010 Revised 21 April 2010 Accepted 4 May 2010 Published Online First 31 July 2010

ABSTRACT In dementia research evidence is mounting that therapeutic strategies that target moderate and even mild Alzheimer’s disease may be missing the ‘therapeutic window’. Given that the neuropathology that leads to Alzheimer’s disease probably begins somewhere between 10 and 15 years before symptoms manifest, many believe that the optimal therapeutic strategy would target persons in the earliest phases of disease development or even earlier. This would include, for example, persons with prodromal Alzheimer’s and even persons who are deemed at risk. Given the nature of research involving the central nervous system, it is conceivable that some therapeutic investigations may involve an increase over minimal risk. This paper examines how, in dementia research, at-risk persons, although healthy, bring multiple and intersecting vulnerabilities to the prospect of research participation even though they are clinically healthy. Current guidelines for research ethics may not provide adequately for the nuances of ‘healthy individuals’ and their possible vulnerabilities. In the context of neurodegenerative disease, the fact of being ‘at risk’ alters the vulnerability profile in significant ways. While healthy persons who are at risk of developing dementia may not appear to warrant placement in the research category of vulnerable participants (alongside prisoners, pregnant women and children) careful regard for the vulnerabilities that arise as a result of the intersecting circumstances of being healthy and at risk of an incurable disease are worthy of increased attention and consideration, particularly as the research effort for the increasingly prevalent disease of Alzheimer’s moves forward.

The number of persons afflicted by dementia, particularly Alzheimer ’s disease, is increasing steadily, with projections in North America of well over 25% of the population over the age of 65 years by 2041.1 Despite extensive funding and research efforts, no effective therapy for Alzheimer ’s disease exists. The need for research leading to more effective diagnostic instruments and therapeutic interventions for this increasingly prevalent disease is widely recognised. One of the emerging challenges for dementia research based on increased understanding of the neuropathology and disease progression is the widely shared realisation that most current therapeutic efforts may be targeting the disease too late in the disease progression to halt or reverse the momentum. Indeed, most studies have tended to identify2 and involve patients with mild to moderate and severe Alzheimer’s disease and consistently have met with disappointing results.3e5 Consequently, the consensus is that in order to develop effective J Med Ethics 2010;36:553e557. doi:10.1136/jme.2010.036335

interventions that target the disease at a stage early enough in the disease progression,6 it will become necessary to involve persons who may have mild (or precursor) symptoms, are pre-symptomatic, or are merely at-risk. Some of this research, partly by virtue of its targetdthe central nervous systemdwill necessarily be classified as involving some increase over minimal risk, for example lumbar puncture, which may represent a minor increase over minimal risk. The ethical challenges in conducting research with this population are complex, triggering issues attendant to the combination of characteristics of this group, that is being ‘at risk’ and ‘healthy’7 (at least in the sense that they do not have a disease diagnosis). This article explores the ethical issues and implications of the involvement of at-risk individuals in dementia research that involves some increase over minimal risk, and shows that a unique constellation of issues arises due to the intersection of multiple categories of vulnerabilities. That is, vulnerabilities of ‘healthy’, ‘at risk’, and ‘ill’ participants may all be present in the same individual. First, a brief background is provided on the state of current dementia research and how it presents unique challenges. Second, the types of challenges and vulnerabilities that emerge in this research context for at-risk healthy individuals are explained. The paper then examines how the intersection of these vulnerabilities may generate different types of ethical concerns than any one of them alone, and concludes that deliberate regard for the ethical complexities of involvement of at-risk healthy individuals in studies on incurable disease is essential.

DEMENTIA RESEARCH: REACHING THE THERAPEUTIC WINDOW There have been a number of important developments in dementia research, most of which in some way point to the need for greater understanding about the very early stages of neurodegeneration. Particularly of interest for the development of therapeutic interventions has been the progress made in the ability to identify subclinical and even presymptomatic biomarkers for dementia, albeit not conclusively. In conjunction with a battery of neuropsychological assessments, several important biological markers have been identified that allow for the detection of changes in the brain that may signal progression towards Alzheimer ’s disease. The introduction of Pittsburgh compound B8 in 2004, which permits the use of positron emission tomography scans to identify the location and quantity of beta-amyloid plaques, a pathology strongly (but not exclusively) associated with 553


Research ethics Alzheimer’s disease, is considered a major advance in dementia research. Also significant has been the identification of biomarkers in the cerebrospinal fluid, thus allowing for the identification of potentially clinically significant neurochemical abnormalities. These and other developments in neuroimaging of structural and functional changes associated with the disease are important additions to previous discoveries (eg, APOE 4, tau and presenilin genetic mutations), in moving closer to the earlier identification of the disease or its precursors. These assessments of risk of cognitive decline are conducted sequentially, usually beginning with the least invasive, e.g. neuropsychological tests. More invasive tests may be subsequently ordered to improve the precision of risk assessment. The discovery of biomarkers, genetic associations (particularly those demonstrating high penetrance, eg, early-onset familial Alzheimer’s disease), and patterns of cognitive deficits already facilitate the identification of elevated risk or probable Alzheimer’s. Moreover, in 2007 a proposal was put forth for new research diagnostic criteria for Alzheimer’s disease that would include the prodromal stage (ie, before frank onset), thus including some forms of mild cognitive impairment (MCI).9 In addition, in February 2010 the proposed revisions for the Diagnostic and Statistical Manual of Mental Disorders version V were released, which included a significant modification under the category of Alzheimer’s disease subtype of major or minor neurocognitive disorders and subtypes.10 This proposed modification would permit the inclusion of early stage cognitive impairment that follows certain patterns and is accompanied by evidence of Alzheimer ’s pathology in Alzheimer ’s diagnosis, even as researchers recognise that pathological evidence of disease can be present in an individual who experiences cognitive health. Nevertheless, this is unlikely to include persons who are merely at risk. Because the proposed diagnosis requires a showing of evidence of Alzheimer ’s pathology and/or aetiology, persons who would receive a diagnosis under the expanded criteria may not be considered ‘healthy’,11 rather they have some kind of cognitive impairment, the future of which is likely to be the onset of Alzheimer’s disease. This claim, however, is not uncontested. Some question the certainty with which this progression can be ascertained at this stage, challenging that such a diagnosis precedes sufficiently robust scientific findings. Nevertheless, diagnosis earlier in the disease progression, if accurate, would facilitate the investigation of therapeutic strategies that target certain patterns of MCI rather than frank onset. In short, while some progress has been made in identifying and eliminating unsuccessful therapeutic strategies, the consensus is that a primary reason for the lack of success is that the therapeutic window is actually earlier than current research has targeted. In the light of relatively recent successes in basic science and ‘failures’ in drug trials (for example trials that do not show statistically significant therapeutic benefits but nevertheless do advance the science by showing that a potentially promising strategy ultimately does not work), the importance of the therapeutic window has taken centre stage, accompanied by speculation that researchers may be missing that ‘therapeutic window’. While the proposed Diagnostic and Statistical Manual of Mental Disorders version V would facilitate a shift in reaching the purported therapeutic window, presumably the neuropathology, even at this stage, is underway. Consequently, the involvement of individuals who are healthy, but at risk are of interest to researchers. Yet, involving this population in research that involves any increase over minimal risk raises a number of complex ethical issues.12 554

INTERSECTING VULNERABILITIES The interest in involving individuals without a dementia diagnosis is increasingly of scientific interest in the effort to identify effective strategies to arrest, slow down, or prevent the progression of Alzheimer’s disease. Indeed, several studies have sought to test the effectiveness of preventive strategies among healthy individuals.13 However, when this endeavour involves more than observation,14 15 it carries some non-obvious ethical concerns. Indeed, the co-existence of being ‘healthy’ and being ‘at risk’ combine to create a constellation of ethical considerations rooted in the complex intertwining of the current enjoyment of health, the threat and fear of serious untreatable illness and core uncertainty about the future. Together, these factors trigger concerns about therapeutic misconception (the failure of research participants to appreciate that the objective of the study is to gain scientific knowledge and is not the same as receiving individualised treatment)16 and voluntariness on the one hand, and about the appreciation of risks and consequences of study involvement (including genetic testing17 18 and receiving unwanted information) on the other, all exacerbated by any elevation in the level of risk above minimal that the study may involve. Moreover, it may not be immediately clear to researchers which of these concerns are likely to arise for individual potential participants. These intersecting vulnerabilities merit attention in multiple ways, particularly regarding recruitment, the informed consent process and the return of research results.

SUBJECTIVE VIEW ON THE HEALTH/ILLNESS SPECTRUM Indeed, persons who are at risk and persons identified as possibly prodromal (‘possibly’ because the subclinical symptoms may, in fact, remain subclinical, for example in the case of MCI associated with the normal ageing) may fall anywhere on the spectrum of healthy and ill in their own subjective view. The spectrum of the subjective view of health status can include ‘healthy’, ‘perhaps becoming ill’, ‘about to become ill’, becoming ill’, or even ‘ill’, even though they are without diagnosis or, in some cases, without symptoms. Therefore, unlike for healthy persons entering a phase I trial or desperately ill patients, eg, with late stage cancer entering an oncology clinical trial, for persons at risk, by virtue of the presence of subclinical features or no symptoms at all, there is no objective indication of their health/illness status, only that they could be either healthy or ill. In essence, they fall into a category ‘in between’. This at-risk status moves them to the margins of good health, yet cannot fully justify inclusion in a disease category, leaving them somewhere in between good and ill health. Individuals in this ‘in-between’ category are uniquely positioned to possess a range of vulnerabilities,19 but quite atypically, with no obvious or predictable indications of what those vulnerabilities might be for any given individual prospective participant. This is further complicated by the variable influence of mood and personality.

IMPACT ON INFORMED CONSENT PROCESS This uncertainty of the at-risk status adds to the complexity of protecting vulnerabilities in the informed consent process. Given the spectrum of possible vulnerabilities20 21 that may attend the circumstance of being apparently healthy but also at risk of a devastating, dreaded disease with no cure, the informed consent process warrants particular consideration. However, determining how the consent process should accommodate the situation of intersecting vulnerabilities presents some challenges. Indeed, the subjective view of potential participants is J Med Ethics 2010;36:553e557. doi:10.1136/jme.2010.036335


Research ethics unknowable by research personnel beforehand, leaving researchers to guess, generalise, or specifically enquire in order to attend to the concerns and perceptions of individual participants. Unlike trials that involve healthy individuals who have no personal interest in the outcome of the study, at-risk individuals are likely to be invested in the study for personal reasons, albeit to varying degrees, again based on one’s subjective view. This personal ‘investment’ in the study holds the possibility of skewing or affecting the otherwise presumably neutral view and assessment of study risks that a healthy person who is not at risk might have. In whatever way the at-risk individual’s view or assessment is altered by his or her at-risk status, vulnerabilities emerge that would not be present for an individual who is not at risk. However, precisely which vulnerabilities these might be may not be readily apparent. Arguably, in this respect, the process is quite different from dealing with very sick or desperately ill participants,22 as the informed consent process23 for this group can reasonably anticipate the possibility, if not the probability, of a therapeutic misconception based on a ‘last hope’.24 In contrast, the involvement of healthy persons who are merely at risk presents yet a different set of issues, for there may be a form of therapeutic misconception that may be motivated by the fear of developing the disease as well as hope for a preventive effect or future curative result if they do. This unrealised spectre can motivate a range of attitudinal responses relevant to the research context, and may hinge on several factors, including the robustness of the risk assessment, the penetrance of any genetic disease mutation, personal experience with others with the disease and the general worldview (eg, glass as half empty or half full). Healthy individuals who are at risk because of a family history or evidence of biomarkers suggestive of a prodromal state, for example, may thus come to the research context with nonapparent vulnerabilities arising from their at-risk status. This may be exacerbated by the societal regard of at-risk persons as being closer to sick than those who are not at risk. In short, because the subjective view of each potential at-risk participant influences the vulnerabilities for which the individual may need ‘protection’, researchers must attend to all of these aspects25 and accommodate the unpredictable subjective view of one’s health state and the vulnerabilities they may carry into the research process as a result.

MORE THAN MINIMAL RISK RESEARCH Some research on the earliest stages of dementia, MCI, or aimed at prevention may involve some increase over minimal risk. This increased risk raises additional ethical issues regarding the riskebenefit ratio, disclosure and safety. In dementia research some of the likely candidates for experimental intervention in clinical trials with greater than minimal risk will involve a lumbar puncture (to derive cerebrospinal fluid). Also, a variety of pharmacological agents designed to hinder the creation or build-up of amyloid plaques, for example, could be introduced in clinical trials with individuals with subclinical probable Alzheimer’s or highly correlative Alzheimer ’s biomarkers. While the lumbar puncture may be viewed as low on the scale of increase over minimal risk, with headache being the most common side-effect in a small percentage of individuals, different pharmacological agents carry a variety of side-effects that could be classified across the spectrum of acceptable, but more than minimal, risk. These could include nausea, dizziness and diarrhoea, on the mild end of the spectrum, but which could become more problematical as disease symptoms progress. Moreover, some pharmacological agents may have more serious J Med Ethics 2010;36:553e557. doi:10.1136/jme.2010.036335

side-effects and, indeed, at least one trial has been halted as a result of safety concerns.26 It is conceivable that more serious but unknown risks could also result from long-term effects of neurochemical changes triggered by therapeutic agents. In short, although more than minimal risk levels in dementia research may gravitate towards the low end of increase over minimal risk, as with the lumbar puncture and mild drug side-effects, the degree of increase over minimal risk is less predictable with experimental pharmacological agents. Consequently, for healthy participants who are at risk and may never develop the disease, there must be a heavy emphasis on safety and disclosure. However, because they are at risk, some justification for the calculation of possible ‘benefit’ may be appropriate. The complexity of the research posture of these individuals is further illustrated by the involvement of at-risk individuals who are, in fact, healthy and will not develop the disease, for example persons with MCI associated with normal ageing, in phase II and III trials in which they are exposed to a trial intervention that exposes them to risk but holds no possibility of benefit.

A GAP IN THE GUIDELINES Placing these individuals in one category or the other meets with numerous challenges as the research ethics guidelines do not appear to address individuals in this situation. For example, in the USA the Common Rule refers to ‘vulnerable populations’ and ‘subjects likely to be vulnerable to coercion or undue influence’27 and specifically refers to prisioners, pregnant women and children, mentally disabled persons,28 and economically or educationally disadvantaged persons.27 Healthy individuals who are at risk would not receive consideration of their vulnerabilities as a result of this status under any of the Common Rule categories. The Council of International Organisations of Medical Sciences (CIOMS) provides for ‘Research involving vulnerable persons’ in guideline 13, and defines vulnerable persons as ‘those who are relatively (or absolutely) incapable of protecting their own interests’ by virtue of ‘insufficient power, intelligence, education, resources, strength, or other needed attributes’.29 The scope of this definition also does not address the situation of healthy persons who are at risk. The penultimate paragraph of this CIOMS commentary refers to ‘persons who have serious, potentially disabling or life-threatening diseases’ as being ‘highly vulnerable’. However, this would neither recognise nor include persons who are at risk of a serious illness. In addition, the commentary recognises the elderly as potentially vulnerable, but focuses on the acquisition of ‘vulnerability-defining attributes’ such as ‘the development of dementia’. However, persons at risk fall in between these categories and so escape regard for their vulnerabilities. The Declaration of Helsinki offers little more in the way of providing for persons at the intersection of good health and being at risk. Its closest reference to ‘economically and medically disadvantaged’30 as vulnerable could not reasonably be construed to include those who have not yet been diagnosed with a disease. Indeed, at-risk healthy individuals who are considering participation in research involving more than minimal risk receive no regard for their vulnerabilities arising out of their at-risk status under any of these guidelines. Protections for healthy individuals do not involve a riskebenefit calculation (beyond generalisable knowledge), nor do they involve concern for a therapeutic misconception, which is a particularly prominent possibility in a population that is at risk of an incurable disease that essentially wipes out one’s personality and identity, and that will inevitably result in death. 555


Research ethics In essence, the intersectionality of vulnerabilities plays an important role in the analysis of risk in research with persons at risk of dementia, and warrants recognition in research ethics guidelines and practice.31 The nature of this fatal and devastating disease coupled with the absence of a cure arguably alters the ethical landscape of this category of healthy persons. Hope and fear may motivate a therapeutic misconception32 in a way that is absent in healthy persons who are not at risk. Furthermore, an illness-based perspective may cause healthy at-risk persons to underestimate and underappreciate the risks of research, especially if the study involves more than minimal risk. Consequently, the need to ascertain the extent to which the participant understands and appreciates the risks of the research and whether these risks are in satisfactory proportion to the anticipated gain in knowledge, as well as the speculative nature of any benefit given no cure, is particularly important. With regard to research risk, not only may there be a greater willingness to participate based on a therapeutic misconception, there is also nuance in the riskebenefit calculation not present in research with not at-risk healthy persons in the form of a personal interest in the research outcome.

CLASSIFICATION AND DISEASE STATUS Significant to a determination regarding the acceptability of involvement in more than minimal risk research is whether prospective participants are of the group of persons with the disease under investigation. In particular, many jurisdictions permit the conduct of research involving greater than minimal risk with members of specified categories of vulnerable persons even if there is no prospect of direct benefit if it is likely to benefit the group of persons (usually read as the ‘disease group’) of which the prospective participant is a member.33 General considerations stating that ethical justification may be found if ‘the research is intended to obtain knowledge that will lead to improved diagnosis, prevention or treatment of diseases or other health problems characteristic of, or unique to, the vulnerable classdeither the actual subjects or other similarly situated members of the vulnerable class’. The circumstance of being at risk and healthy makes this a complex classification to make as the fact of being at risk creates an interest in the disease group and the development of interventions even if they may ultimately not need to avail themselves of these interventions. Nevertheless, the at-risk individual may subjectively and/or prospectively identify with the class of persons that has the disease, and thereby possibly alter the riskebenefit profile and calculation. Yet, despite the emotional and personal burden that being at risk of dementia may sometimes carry, absent symptoms, a diagnosis, or definitively correlative presymptomatic biomarkers, persons who are merely at risk are, in fact, healthy. Furthermore, even though the disease in question is one that eventually involves the loss of capacity, at-risk persons do not lack capacity. Consequently, their decision to participate in more than minimal risk research can, in these ways, be analysed very much like the decision of healthy individuals who are not at risk. Yet, in other important respects at-risk persons carry intersecting vulnerabilities based, at least partly, on the subjective view and the threat of incurable disease into dementia research that do warrant consideration and protection. The case of dementia research and the identification of persons at risk who could ethically be involved in more than minimal research presents some possible resolutions even as it presents this challenge. Indeed, assessment of the earliest stages of Alzheimer’s disease currently uses multidomain assessment tools, including biomarkers, neuropsychological assessments, 556

behavioural criteria and neurochemical and structural changes from an identified baseline. The use of some of these assessment tools may, in time, be used to identify presymptomatic dementia accurately. However, short of conclusive presymptomatic assessment, the mere fact of being at risk genetically, behaviourally, or in other phenotypic ways, perhaps including simply advanced age, may be sufficient to cause some individuals to have a strong interest in a particular research project and influence decisions to participate and the assessment of risks that their objective health status may not make obvious. Therefore, mere membership in a family with a history of dementia, even absent other highly indicative markers, may be sufficient to invoke consideration of a riskebenefit ratio, at least in the prospective participant’s mind. For this ‘category in between’, due and deliberate consideration of individual reasons for research participation is necessary if the research involves any increase over minimal risk. In this way, researchers can attend to the vulnerabilities that may not otherwise be apparent.

CONCLUSION The involvement of persons in the early stages of or at elevated risk of cognitive decline in dementia research is likely to increase in the coming years given the projected demographics of the disease. It is critical to recognise that these individuals, although healthy, face the possibility of an incurable, devastating and ultimately fatal disease. As such, a range of non-obvious factors may be motivating participation and unduly affecting the assessment of research risks and the consequences of participation. While we do not normally regard this population as being vulnerable, the intersection of being at risk and healthy and the spectre of an incurable fatal disease can result in vulnerabilities that are not accommodated in current research ethics guidelines. Importantly, this phenomenon is not limited to Alzheimer’s disease but may apply to ascertainable risk for any incurable serious disease. This paper points to the need for careful consideration of the vulnerabilities inherent in this situation in both research policy and practice. Acknowledgements The author wishes to acknowledge support by the Brocher Foundation and CIHR. The author is very grateful to the anonymous reviewers for their comments and suggestions. The author also thanks Gaia Barazzetti for thoughtful discussions about this topic. Funding The author is visiting a Wellcome Trust-funded institution, but receives no funding from them. In addition, she received financial support from the Brocher Foundation and CIHR. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.

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