Successful trial enrollment faces many barriers, and most AD trials struggle to enroll. The ADCS trial of docosahexaenoic acid (DHA) enrolled 400 mild-to-moderate AD patients in 8 months, 10 months ahead of schedule, making it unique among AD trials. The agent tested in this trial funded by the National Institutes of Health was considered safe, allowing less restrictive inclusion and exclusion criteria. The trial also employed a 60/40 alternate allocation ratio toward active treatment. The factor that may have had the greatest impact on trial recruitment, however, was that it was conducted during a period in which few other trials in mild-to-moderate AD were recruiting and competition for subjects was minimal (Joseph Quinn, Oregon Health and Science University, Portland, OR, USA, personal communication).
As discussed, successful recruitment means more than just timely fulfillment of enrollment goals. Trial participants should be representative of the greater AD population. The mean age of participants in the DHA trial was 75.6 years. Fifty-three percent of participants were female. These demographic factors are fairly representative of the greater AD-suffering population. Participants in the DHA trial averaged 14.1 years of education. The over-representation of highly educated participants is common among AD trial populations [14
] and stands in stark contrast to epidemiologic studies, which consistently demonstrate that less than 12 years of education is a significant risk factor for AD [15
]. In the DHA trial, 90% of participants were Caucasian. Faison and colleagues [17
] examined the race of AD trial participants, comparing 737 ADCS trial participants with 10,800 industry- sponsored trial participants. The authors found that only 10% of ADCS and 3% of industry-sponsored trial participants were non-Caucasian [17
]. Given that African-Americans and Hispanics are at greater risk for AD than Caucasians [18
] and that the proportion of AD sufferers who are of minority race or ethnicity will increase faster than that of Caucasians in coming decades [20
], the low rates of minority enrollment in trials must be improved.
Among study partners in the DHA trial, 65% were female and 68% were spouses of the participant. The patient's primary caregiver most often fills the role of study partner and there are roughly 11 million persons in the US caring for a dementia patient. The majority of AD caregivers are women. Only a fraction of caregivers in the US, however, are spouses. The majority of caregivers are non-spousal family members, including primarily those who care for a parent or a parent-in-law [20
]. The high representation of spousal caregivers in AD trials is striking and important. Trials offer patients and families an opportunity to feel active and involved in their medical care and in medical science's attempts to help them, others like them, and future generations. Many enroll in AD trials, however, in pursuit of therapeutic benefit. Spousal caregivers may have greater motivation than do adult children caregivers to pursue new therapeutic options. Alternatively, there may be increased barriers to participation for adult children caregivers, who are more likely to be working full-time, more likely to have young families, and thus less likely to have the scheduling flexibility to participate in clinical trials in the 9-to-5 clinic schedules in which they are generally conducted.
The overall differences between the enrolled population and the general AD population are troubling. They suggest that the barriers to recruitment and retention significantly shape the population under study and call into question the notion that the results of AD trials will be broadly applicable beyond a given study. We will next examine the various barriers to recruitment of AD trial participants, including the patient and the caregiver study partner.
Barriers related to the Alzheimer's disease patient-caregiver dyad
The decision to enroll in an AD trial is made by two people: the patient and their study partner. In this way, recruitment to AD trials is twice as difficult as recruitment to clinical trials that enroll only the patient. Those who choose to participate in a clinical trial commit significant time and energy. This commitment is justified out of hope for personal and societal benefit and trust in the investigator and study site [21
]. The commitment is made with an understanding of given risks and requirements. Both the patient participant and the study partner participant must give informed consent and both must commit to full participation. Of course, patientcaregiver dyads cannot choose to participate unless they are aware of studies. At diagnosis, referral to trials is uncommon [22
]. Thus, participation by those seeing physicians who do not personally conduct trials often requires active pursuit of information about study opportunities. Yet even when the patient and the study partner are aware of trials, they are still likely to encounter several barriers to trial participation. The barriers and facilitators of AD trial enrollment related to patients and caregivers are summarized in Table .
Facilitators and barriers to participation in Alzheimer's disease clinical trials
Barriers related to the Alzheimer's disease patient
Many AD patients who wish to participate in a clinical trial may not be eligible to do so. AD patients are, by definition, older. Older patients are likely to suffer from comorbidities that exclude participation. For example, current trials of immunotherapies exclude participants for a previous infarct (observed via magnetic resonance imaging [MRI]), even if it results in no neurologic sign or symptom. Given the high incidence of overlap between AD and vascular pathology [23
], a substantial number of patients who might otherwise qualify for a trial may fail to be included, because of this criterion.
Older patients, especially in the US, also take a high number of prescription medications, which may similarly exclude participation. Even if these patients do not take an exclusionary medication at screening, trial protocols instruct investigators to enroll only patients whose medication profiles are stable and not likely to change through the course of the study. Protocols generally include patients taking AD medications, although these medications are subject to the same requirements. Thus, when enrolling mild patients who take only an acetylcholinesterase inhibitor (AChEI), the investigator is forced to consider whether to enroll the patient or start memantine (approved only in moderate-to-severe disease) to ensure stability through the course of the trial. Choosing the latter forces a delay in trial initiation and increases the likelihood that the patient will not be enrolled due to study closure or another reason.
Previous participation in an AD trial may exclude enrollment. Late-stage trials generally exclude participants of earlier-phase studies of the same drug. Similarly, most trials of active or passive immunization now exclude patients who have previously participated in a trial of any AD immunotherapy. In fact, for some ongoing trials, choosing to enroll means lifelong participation in one and only one trial. For example, the ADCS trial of nerve growth factor gene transfer aims to follow participants to autopsy and, given that subjects receive a therapy that is anticipated to deliver its therapeutic effect for as long as the neurons receiving it survive, being accepted into other trials is unlikely for recipients of the active therapy.
Some patients may be unwilling or unable to participate because of the procedures involved in a study. Individuals with pacemakers cannot undergo study-required MRIs and thus are excluded from trials that require imaging to ensure safety or use volumetric measures as mandatory outcomes. Many patients experience anxiety related to study procedures such as lumbar punctures. One phase II investigation of a gamma secretase inhibitor in prodromal AD is enrolling participants in the randomly assigned treatment trial only if they meet specific criteria related to cerebrospinal fluid protein analysis. Individuals unable or unwilling to undergo lumbar puncture are ineligible. Neuropsychological testing remains the hallmark of AD trials, co-primary outcome measures for all registration trials include one cognitive measure, and essentially all trials include a broad array of psychometric tests. For many trials, cognitive testing batteries are limited to the English language. Often, individuals not able to complete cognitive testing in the available languages at a study site are excluded. Such testing may require 3 to 5 hours to complete and can result in frustration and distress for the participant [24
]. In subjects aware of their impairment, the reminder of their cognitive struggles can be overwhelming and may result in an unwillingness to participate.
Not all AD patients are aware of their impairment and those who lack insight may also lack the capacity to give informed consent. Some recent trials of aggressive therapies exclude individuals not able to demonstrate the capacity to provide consent. In these trials, the inability to comprehend trial-related procedures and risks is a barrier to participation. The majority of AD trials, however, facilitate participation by permitting a legally authorized representative to give the informed consent on behalf of a patient who lacks the capacity to do so for him- or herself. Most AD patients wish to be involved in the decision of whether to participate [25
], and dyads that enroll in trials are likely to reach a joint decision. Although it is not clear how often it occurs, disagreement between patients and caregivers about participation can be a barrier to enrollment [21
Barriers related to the study partner
Patients who do not have a suitable study partner cannot be enrolled in AD trials. The study partner must be an individual familiar with the patient's medical and personal situation and the primary caregiver most often fills this critical role. At screening, the study partner provides an accurate medical history. Following enrollment, they provide transportation to study visits and serve as informants in a variety of study procedures and outcome measures. Between study visits, they monitor study and medication adherence.
The role of the caregiver in the decision to participate in an AD trial is as important as that of the patient. Often, caregivers choose to participate in AD clinical trials out of hope for medical benefit for the patient [21
]. Other motivations include desperation resulting from a lack of other treatment options [21
] and a desire to help medical science pursue a cure [21
]. Trials offer the opportunity to interact with AD experts and access to new technologies that might not be covered by insurance.
If a study partner faces insurmountable barriers to participation, then it is unlikely that the patient will participate. Caregivers who decline participation cite a variety of factors that lead to their decision. Some caregivers cite the need to travel to the study site [21
], and offering car services to facilitate transportation or performing at least a portion of study visits in the home increases the likelihood that caregivers will support a decision to participate [31
]. Individuals who report travel as a barrier, however, are not necessarily those who reside furthest from study sites. This suggests that, at least for some caregivers who decline participation, emotional and attitudinal factors about the logistics of travel play a large role.
Caregivers also face emotional burdens [32
]. They often cite the fear of side effects for the patient as a barrier to participation [21
]. Many caregivers do not distinguish risks or benefits for the patient from risks or benefits for themselves [21
]. The patient is most often a spouse or parent, and the caregiver does not wish to increase the patient's medical burden. Furthermore, increased medical burden for the patient is increased burden on the primary caregiver.
Finally, some caregivers cite the risk that the patient will not benefit from participation as a barrier to enrollment [27
]. Some caregivers who decline enrollment cite doubts about the potential efficacy of the agent under investigation as reason for refusing participation [28
]. These caregivers may defer participation in one trial to participate in another, more promising study. The same individuals are likely to cite the 'risk' of placebo as a deterrent to participation.