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Dementia affects an estimated 36 million people worldwide, the majority of whom will have Alzheimer's disease (Ballard et al., 2011). Currently, there are licensed pharmacological therapies, which confer modest but significant and cost-effective symptomatic benefits (Ballard et al., 2011), but there no effective disease-modifying treatments, and some of the most promising disease-modifying compounds have failed to show efficacy in phase III drug trials, despite promising pre-clinical data (Karran et al., 2011). An often cited reason for this is that in the mild to moderate dementia stage of Alzheimer's disease, when the drugs have been traditionally tested, the underlying pathology in the brain is at an advanced and irreversible state (Petersen, 2009; Extance, 2010; Sperling et al., 2011). Hence, there is significant interest in conducting clinical trials earlier in the disease course, particularly at stage of Mild Cognitive Impairment (MCI) before the onset of dementia including significant functional impairment and when the pathology may be less advanced and modifiable. Diagnostic biomarker tests now allow for detection of Alzheimer's pathology in patients with MCI, with high (but not absolute) accuracy (Sperling et al., 2012; Jack et al., 2011; McKhann et al., 2011), and research criteria have been developed for early Alzheimer's disease (Dubois et al., 2007, 2010), paving the way for identifying prodromal Alzheimer's disease patients to participate in clinical trials that may slow or halt progression to the clinical symptoms of dementia.
One promising avenue for drug development has been antibody therapies raised against amyloid-β peptide (Aβ). Several phase II trials of different anti-amyloid antibodies under development have shown they can reduce Aβ levels in mild to moderate Alzheimer's disease (Rinne et al., 2010; Ostrowitzki et al., 2012; Siemers et al., 2010) and have a safety profile supporting their progression to efficacy phase III trials. However, phase III trials of the immunotherpapy treatments bapineuzamab and solanuzemab have already failed to demonstrate significant benefit (Corbett et al., 2012), so the efficacy of this class of compounds is uncertain. In addition, participating in an immunotherapy clinical trial is an extensive undertaking involving multiple medical examinations, regular injections, magnetic resonance imaging and lumbar punctures over several years. Whether an individual will derive benefit from the drug is unknown, and immunotherapies have been found to be associated with significant side effects, including pain or allergic reactions where the injection is given. In 5–10% of cases, more serious adverse events including vasogenic edema and microhemorrhages have been reported Sperling et al. (2012).
For trials of MCI patients with early or prodromal Alzheimer's disease, there is the additional issue of undertaking biomarker-based diagnostic tests for Alzheimer's disease as part of the trial ‘screening’ process. Many ethical considerations surround the use of early diagnosis tools that exist in the absence of proven disease-modifying therapies (Prvulovic and Hampel, 2011; Singh and Rose, 2009). Moreover, evidence suggests high but not absolute diagnostic accuracy of biomarkers for incipient Alzheimer's disease in MCI, with sensitivity and specificity around 85–90% (Hansson et al., 2006; Mattsson et al., 2010), thus an enduring risk of misdiagnosis exists.
A favourable risk–benefit ratio is an ethical requirement for clinical research; not only must risks be minimised and potential benefits enhanced but also the potential benefits to individuals and the knowledge gained for society must be considered to outweigh the risks, including considerations such as the strength of evidence from preliminary trials. However, these variables are difficult to quantify, and there is no accepted formula to determine whether the potential benefits ‘outweigh’ the risks (Emanuel et al., 2000). It is vital that the views of people with memory complaints and their families are at the centre of informing ethical debate and conduct of clinical trials in this area. Embedding the priorities and concerns of service users in all stages of translational research promises not only to enhance trial recruitment and retention but also to inform the development of therapeutic interventions that are acceptable to, and valued by, the individuals that need them (Callard et al., 2012).
We propose to build upon research examining attitudes towards Alzheimer's disease trial participation among family carers and well older adults (Karlawish et al., 2001; Williams et al., 2010) to explore how people with mild memory complaints themselves feel about learning their biomarker status and participating in an immunotherapy clinical trial. We sought to explore these key issues using an example of an immunotherapy clinical trial, because of it being topical and having a complex risk to benefit profile.
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We conducted a series of focus groups to explore the level of risk that people with memory problems and family carers would be prepared to take to participate in clinical trials of potential new therapies. This allowed us to examine the perceived acceptability, feasibility and conduct of future clinical trials in this area (Donovan et al., 2009). Favourable ethics permission for the study was obtained from the London Central National Research Ethics Service Committee.
Participants, in accordance with the design of immunotherapy clinical trials, included people that have a diagnosis of MCI and close relatives. The views of former carers of people with Alzheimer' disease were also sought in a separate focus group (Group 1) to explore how this experience might influence attitudes towards trial involvement, which also allowed for some refinement of the topic guide. Former carers were recruited through the Alzheimer's Society Research Network, and people with mild memory complaints were recruited via an Alzheimer's Society run peer support project. Individuals attending the support group could only do so via referral from a local memory service and therefore had been assessed by a consultant as having a ‘mild memory complaint’. Efforts were made to recruit participants with a variety of socio-demographic characteristics, including age, gender, ethnicity and relationship to the person with memory problems, so we were able to investigate how individuals weigh up the perceived risks and benefits of participating in a hypothetical immunotherapy clinical trial from a range of perspectives (Table 1). The discussion groups continued until data saturation was achieved and, no new themes were emerging from the data analysis.
Table 1. Demographic characteristics of focus group participants
|Age of person with memory problems (years)||69||45–86|
|Time since diagnosis (years)||1.9||1–4|
| ||N (%)|| |
|Type of participant|| |
|Person with memory problems||14 (50)|
|Current family carer||8 (29)|
|Former family carer||6 (21)|
|Gender of person with memory problems|| || |
|Relationship of carer to person|| || |
Focus groups were used to help participants explore and clarify their views and provide insight into the decision-making process (Kitzinger, 1995). Participants were sent a briefing document in advance of the focus group to allow them time to consider the issues. This was created using published and unpublished trial protocols of immunotherapy trials for Alzheimer's disease. The participant information was designed to be general about immunotherapy as opposed to specific about one particular agent in this class of drugs and included the following: details of the tests used to identify biomarkers in the screening process; a description of the clinical trial including duration, tests involved and number of study visits; and a discussion of the side effects that have been published for anti-amyloid therapies. A member of the research team knowledgeable about clinical trials in dementia provided a short presentation summarising what participation in an immunotherapy clinical trial might involve and answered all technical questions, which allowed the discussion to progress. Discussions were led by a social scientist (V. L.). At the time of conducting the focus groups, no clinical trials were actively recruiting prodromal patients in the UK, although participants were informed that such studies were under consideration and likely to be available in the near future. Therefore, discussions focussed on a hypothetical trial of immunotherapy for people with mild memory problems (Box 1). The scope of the topic guide was guided by an initial conversation between Roche Products Ltd and Alzheimer's Society. The topic guide was further developed by an iterative process between clinicians (C. B.) and social scientists (V. L. and J. M.). Each focus group lasted approximately 90 min, was audio-recorded and transcribed verbatim. All data were anonymised.
Box 1: Development of topic guide
Topics of investigation included:
- whether individuals would be prepared to participate in an immunotherapy clinical trial
- the main areas of concern; whether individuals would want to learn that their memory impairment had a likely underlying Alzheimer's pathology
- whether the potential benefits of the therapy justify the risks involved
- and areas of misunderstanding or confusion where better information is needed
The topic guide was amended iteratively and aimed to follow the participants’ own concerns.
A systematic analysis procedure, drawing on the grounded theory approach (Glaser, 1978), was used to generate an increased understanding of how participants weigh up the possible risks and benefits of an immunotherapy clinical trial. Grounded theory is primarily inductive, and themes are derived from the data rather than from existing theory. Data collection and analysis proceeded simultaneously, and emerging themes were tested out in subsequent discussion groups, for example, the expressed concern that participation in a clinical trial could ‘upset the balance’ was explored in later groups. Two of the research team (V. L. and J. M.) read through each focus group transcript independently and identified and labelled the data with descriptive codes. They then compared their coding strategies and discussed any instances of disagreement until a consensus was reached. One researcher (V. L.) then used the ‘constant comparison’ method to delineate the similarities and differences between the codes to enable a final coding framework to be developed. Codes were grouped together to form higher-level conceptual categories, which were verified and refined as the analysis proceeded. The transparency of the research process was increased through theoretical memos, which documented thoughts, interpretations and questions about the data, the ongoing development of categories and their relationships (Glaser, 1978).
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Twenty-eight participants took part in four focus group discussions (FGD 1: n = 1 person with memory problems, two carers, six former carers; FGD 2: n = 2 people with memory problems, four carers; FGD 3: n = 4 people with memory problems; FGD 4: n = 7 people with memory problems, two carers). Strongly defined views emerged across the groups that provided insight into perceived personal benefits of the screening process and study drug, the demands of taking part, attitudes towards side effects, information needs and the decision-making process (Table 2). These themes will now be discussed in depth. Direct quotations are provided in boxes; pseudonyms are used for clarity only.
Table 2. Summary of key themes
|Attitudes towards the screening process||Perceived benefits of the screening process||The ‘screening’ stage was identified as one of the primary benefits of participating in the trial; participants were keen to know the cause of their condition and what the future may hold.|
|Potential benefits to society were recognised but were generally not considered reason enough to participate in a clinical trial.|
| ||Stigma of dementia||Former carers were alone in expressing concern about being labelled with ‘dementia’.|
|Perceived benefits of study drug|| ||The majority of participants appeared to assume that receiving the study drug would be beneficial.|
|There was a consensus that limiting further cognitive deterioration was sufficient benefit.|
|Receiving the placebo was considered a highly undesirable outcome.|
|Demands of taking part||Widespread concern||The use of magnetic resonance imaging scans and lumbar punctures provoked anxiety across the groups.|
|Whether the study demands were construed as off-putting or tolerable in part reflected how concerned participants were about their cognitive or their physical condition.|
| ||Tolerable ‘v’ off-putting||Some participants spoke at length about the negative impact of their memory problems on their lives. Many feared that they would get progressively worse and were keen to be involved in a clinical trial.|
|Others appeared more preoccupied with physical complaints, which had often caused pain, discomfort and distress. They feared that taking part in a clinical trial might upset their balance in managing their medication, physical health and memory problems|
|Attitudes towards side effects||Limited concern||General acceptance that all medications/treatment have associated side effects.|
|Assumption that drug must be sufficiently ‘safe’ to have reached this stage.|
|Information needs|| ||Further information was considered necessary regarding the precise role of the ‘study partner’.|
|Further information should be given about the design of the trial, in particular, the ‘screening’ and how suitability would be established.|
|Participants required both written information and the opportunity to discuss questions and concerns.|
|Making the decision||Step-wise approach||Participants described, first, undertaking the ‘screening’ to gain a better indication of the underlying cause of memory problems and subsequently evaluating whether they wish to be involved in a trial.|
| ||Joint decision with family||People with memory problems expressed clear preferences about participating in a clinical trial but agreed that it would have to be a joint decision with their family.|
Attitudes towards the screening process
Perceived benefits of the screening process
One of the most prominent themes to emerge in the focus group discussions was the sense of uncertainty surrounding the cause of individual's memory problems. Participants sought clarification regarding whether these could be a side effect of medication or other physical conditions, or a consequence of age, depression, anxiety or, as feared by many, dementia. People with memory problems and current carers indicated that one of their primary motivations for becoming involved in the hypothetical clinical trial would be to have access to pre-trial screening to find out whether the person's memory problems had an underlying Alzheimer's pathology (Box 2, Lillian).
Box 2: Direct quotes from study participants on the screening process and study drug
Perceived benefits of the screening process
Lillian: I would rather know.
Janet: Could you deal with it Lillian?
Lillian: I could deal with it. I have dealt with a lot in my life, so it would be just another thing for me to deal with, and I would rather deal with it than not know and then all of sudden realise I am not well. And I feel sure about that.
Julie: Because I am, sorry, but younger than most people here [laughter] I would want to know and then if I could do anything myself to improve my memory, that would help.
Perceived benefits of study drug
Mary: My feeling would be if the quality of life was marked and obvious, even for 3 months, I know my husband would have snatched it off a tree. (Group 1)
Josephine: You know I check and double check to make sure everything is written down, so if I can just maintain where I am. That would be great too if I get better, you know…. but as long as I know it's not going to be worse than what I am getting now. (Group 2)
Minimal concern about side effects
Dennis: All tablets are risk taking aren't they? I mean the doctor can look in her little book and say, “This is what I am giving you.” They don't suit everyone do they? (Group 3)
Stigma of dementia
Here, the comments of people with memory problems and current carers contrasted with those of former carers who expressed strong reservations about whether they personally would want to address cognitive difficulties at that early stage. Former carers were alone in discussing issues of stigma, and the unwelcome practical and emotional implications that receiving a diagnosis might hold. They acknowledged that it was difficult for them to put their extensive experience of Alzheimer's disease to one side. Former carers were more likely to consider participation in terms of the potential benefits for future generations and society as whole. Although other participants recognised that taking part in a trial of this sort could benefit others, this was not in itself considered an adequate reason to accept the potential personal risks of becoming involved. Individuals were clear that first and foremost, it would have to be in their own interests.
Perceived benefits of study drug
There was a strong impression across the focus groups that participants assumed the study drug would be beneficial and few sought information regarding the effectiveness of the intervention. Concerns related not to whether the study drug would work but the risk of being randomised to the control group and of receiving the ‘dummy’ (placebo) drug instead. Participants explained that this would leave them feeling angry and disappointed. Yet it was also evident that the majority of participants both understood and accepted that the intervention did not promise to improve their cognitive state but simply to limit further deterioration. There was consensus that maintaining their current condition would be benefit enough.
Former carers concurred that even modest benefits would be highly valued (Box 2, Mary).
In the majority of instances, the perceived benefits of the intervention itself did not present as a decisive factor in the decision-making process. Rather, participants seemed to concentrate on whether the person with memory problems was eligible for the trial and/or whether they could tolerate the demands of taking part. If these criteria were satisfied, any chance of improvement or delay in deterioration seemed to merit participation (Box 2, Josephine).
Minimal concern about side effects
People with memory problems, former carers and current carers seemed largely unconcerned about the side effects that had been reported in previous studies. Former carers asked questions about the precise stage of current trials and how they were being monitored, yet the majority of participants displayed confidence that the drug must be sufficiently ‘safe’ to have reached this stage in the development process. Moreover, there appeared to be a general acceptance that all medications have associated side effects and may or may not be suited to the individual (Box 2, Dennis).
Demands of taking part
Certain tests and procedures involved in the trial, particularly lumbar punctures and magnetic resonance imaging scans, provoked widespread concern. There were also a large number of questions regarding whether the study drug would be compatible with medication that participants were already taking. Whether the study demands were construed as off-putting or tolerable seemed in part to reflect how concerned participants were about their cognitive or their physical condition. Some participants spoke at length about the negative impact of memory problems on their lives. These individuals, along with the majority of current carers, were highly sensitive to changes in the individual's cognitive state and feared progressive deterioration. They seemed prepared to accept invasive tests in the hope that they might find out more about the underlying cause of the memory problems. They also indicated that they would accept the ongoing demands of participating in the clinical trial if they were considered eligible to take part (Box 3, Julie).
Box 3: Direct quotes from study participants on the demands of participating in the trial
Demands of taking part
Julie: It [lumbar puncture] was painful, very painful but not so painful that I would say, “Well I won't do the tests or anything”. I would have another go.
Moderator: How do other people feel about doing those sorts of tests?
Margaret: I'm alright, I will do it.
Lillian: I'm alright with injections, I have had so many.
Kenneth: Like I said to you with the injection, it's worth a try if you are going to find out, you know what I mean? (Group 4)
Ivy: I don't feel very safe with any more treatment for anything, because I had a back operation 3 years ago, I had, I can't remember what you call it, but it was the arthritis and everything and then the hip, and I am still in a lot of pain, so I just decide to go through with whatever happens to me now. No more, I am managing fine as it is. (Group 4)
Caroline: The thing is if it's once a month is it on a specific day each month, because for us, some of us are working and we would need to take those days off work in order to accompany our parents. Is it on a regular day, like you know with the meetings? Because we know it is always the last Friday of the month, so at least we can organise our time off at work. (Group 2)
Doris: Your children won't be able to go because they are busy. Your children they are busy with their households and demanding jobs, they won't be able to come. It will be difficult for them to attend. (Group 3)
Conversely, other older people emphasised that they were currently coping with their memory problems and frequently mentioned strategies such as making lists that helped them to live independently. Many of these participants were suffering from co-existing physical complaints that caused pain, discomfort and distress. Participating in a clinical trial was generally considered too demanding in this context (Box 3, Ivy).
As these participants were not opposed to finding out more about their condition, they were not prepared to put their wider health at risk to do so. Maintaining the fine balance that they had achieved in managing their medication, physical health and memory problems was considered to be of greater importance. There were few objections to the time commitment that the clinical trial would require, although a recurring issue related to the organisation of the appointments at the study centre. These would need to accommodate other commitments, particularly for ‘study partners’ (family members) who were likely to be working (Box 3, Caroline).
People with memory problems who were attending the focus group on their own gave mixed responses about who could act as a study partner and how feasible it would be for them to do so. Some were confident that this would not be a problem; others were clearly worried about burdening their relatives (Box 3, Doris).
There was consensus that additional information should be given about the role of study partner. People with memory problems were keen to find out who could perform this role and why it was necessary. Carers sought clarification on how the appointments would be arranged and what procedures they should follow in certain scenarios, for example if they observed side effects. The feasibility of travelling to the trial centre was an important consideration. Family members asked a wide range of questions relating to the design of the trial such as how the study drug/placebo would be allocated and what would happen if their relative's cognition deteriorated during the trial. Given the significance that participants attached to the screening process, there was a strong feeling that the study information should specify more clearly what this would involve and how this would establish whether their relative was eligible to take part in the trial (Box 4, Caroline).
Box 4: Direct quotes from study participants regarding their information needs and how they would decide if they were to participate
Caroline: I think we have asked a lot of questions about the tests and so on because it wasn't very clear that after you have had the lumbar and the brain MRI scans some people will actually be told “no, you can't take part” or “yes you can”. (Group 1)
Making the decision
Josephine: For me, for now it's the lumbar puncture and the MRI, that's the one important thing now and then when we know the results that's when the decision will come because then we will know exactly where we are. (Group 2)
Maggie: You give people as much information as they can handle as the individual and the partner or the principal carer and you give them that information and you leave them to make informed choices. I don't think anybody else can make that choice for you. (Group 1)
Finally, a couple of people with memory problems commented that they had found the study information difficult to retain. It was evident that in addition to written information, people with memory problems and family members required the opportunity to discuss their questions and concerns with an informed member of the research team before reaching a decision on taking part.
Making the decision
Participants described a step-wise approach to their decision-making process: first, they would undertake the ‘screening’ to gain a better indication of the underlying cause of memory problems; then, they would evaluate whether they wished to be involved in a trial (Box 4, Josephine).
For the most part, participants with memory problems expressed clear preferences about whether they would wish to take part in a clinical trial of this sort. Yet, the majority also agreed that they would only reach a decision after they had considered the issues with their families. Although not all participants wished to take part themselves, the groups were unanimous that immunotherapy clinical trials should go ahead. The common view was that individuals, with the help of their family, must decide for themselves (Box 4, Maggie).
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There was recognition that the decision to participate in an immunotherapy clinical trial involved weighing up multiple factors, many of which were unknown. However, the majority of participants seemed to have a clear idea about whether they, personally, would wish to take part. One of the primary findings was that people with memory problems and relatives appeared highly motivated to find out more about the underlying cause of the condition, regardless of their desire to participate in a clinical trial. The need for an unambiguous diagnosis frequently dominated the discussion, whereas the potentially negative psychological and legal consequences of learning one's biomarker status were rarely touched upon. Discussion of the ethical considerations of early Alzheimer's disease diagnosis often identifies the risk of provoking feelings of sorrow, stress and despair (Mattsson et al., 2010). Yet the data support evidence that receiving a diagnosis of dementia can engender feelings of relief and reduce anxiety (Carpenter et al., 2008). Although these findings suggest that patients desire further information about the cause and prognosis of their memory impairment, there are still important ethical considerations for clinicians to ensure that appropriate support, services and counselling are available for patients undergoing tests for biomarker status. Sufficient time and attention must be given both to preparing participants for the results and the subsequent discussion of the implications (Prvulovic and Hampel, 2011). These findings also highlight how difficult it is to explain to participants the level of uncertainty that remains regarding the likelihood of progressing towards Alzheimer's disease. Coupled with the belief that they would receive a definitive diagnosis, participants displayed an expectation that they would benefit from the study drug should they agree to take part. This is reminiscent of Appelbaum's central concept of ‘therapeutic misconception’ (Applebaum et al., 1982), which proposes an inclination among participants to assume that research will be designed and executed according to their best interests. Full and repeated descriptions of trial procedures are required, especially among participants who have difficulty in retaining complex information.
The findings suggest that patient perception of risks from participating in a clinical trial of immunotherapy may be different to that of clinicians and regulators. People with memory problems and carers expressed minimal concern regarding the risk of adverse events associated with immunotherapy (Sperling et al., 2012). However, some of the more invasive tests and procedures involved in the hypothetical trial provoked anxiety across the groups as indicated in studies of well older adults (Karlawish et al., 2001). Whether the study demands were construed as off-putting or tolerable seemed in part to reflect how concerned participants were about their cognitive or their physical condition, again illustrating the highly personal nature of this decision. The findings support evidence that individuals with some cognitive impairment remain able to meaningfully evaluate risk/benefit profiles, even in the face of decreased decisional abilities (Kim et al., 2002).
The study also highlights the high level of comorbidity among the target group. People with memory problems and their relatives require clear information regarding the exclusion criteria and whether comorbid medical conditions would prevent them participating. The opportunity to discuss fully their individual concerns with an informed member of the research team would be an essential prerequisite. Establishing a relationship of trust with the trial co-ordinators has been found to minimise concerns about potential risks in other studies (Karlawish et al., 2001). There was little evidence of divergence in views between people with memory problems and relatives who attended the focus group together. Yet, people with memory problems who attended on their own expressed greater reservations about inconveniencing family members and whether they would be able to cope with participating in a clinical trial. This suggests the importance of consulting both the person with memory problems and his or her relative from the earliest stage of recruitment, so that all parties have the opportunity to contribute their views to the decision on trial participation.
Overall, this study shows that the views and preferences of people with memory problems and their relatives can inform the policy and practice concerning the disclosure of biomarker status, the design of clinical trials and the content of trial information. However, some caution should used when interpreting the findings. The numbers involved in this qualitative study are limited, and the views expressed may not be typical of people with MCI or carers. Agreeing to participate in a focus group about immunotherapy clinical trials suggests a degree of interest in medical research and interventions that may not be shared by others. However, efforts were made to explore differences of opinion and to recruit individuals from a variety of backgrounds. Participants articulated strongly defined views ranging from a clear preference to take part in an immunotherapy clinical trial to an equally strong reluctance to be involved. The focus group discussions concerned hypothetical trials, and participants may have expressed different views if they were considering taking part in a live study. However, there was a high level of engagement from all participants, and it was striking that all groups were unanimous that clinical trials of this sort should be allowed to go ahead, regardless of whether they personally wished to be involved. We believe the findings have applicability beyond the context of this research and can help to advance the design of future clinical trials in this area.