Addressing the challenges to successful recruitment and retention in Alzheimer's disease clinical trials

Visit frequency and study length

Decisions related to the total length of a study and the frequency of study visits are guided by study goals and often by concerns over safety. It is logical to expect that the longer the study and the greater the number of study visits, the greater the burden on participants and the more difficult recruitment will be. Trials of agents with high risk profiles or for which the risk profile is largely unknown often require more visits to ensure patient safety. For example, early-phase studies (phase I or IIa) are often shorter (on the order of weeks to months) and require more frequent study visits than later-phase studies. Phase II AD trials of gamma secretase inhibitors have commonly used every-other-week study visits [1], making participation more daunting, especially for individuals who travel great distances to participate. In contrast, late-phase studies (phase IIb or III) that aim to evaluate efficacy are commonly at least 18 months long. These trials generally use study visits every 3 months. Less commonly, the intervention itself necessitates a more frequent rate of study visits. Ongoing trials of some immunotherapies for AD use medication infusions once or twice per month.

Selection of the targeted Alzheimer's disease population

The target population is defined by the inclusion and exclusion criteria that participants must meet to enroll. Inclusion criteria should be designed to enroll only patients who truly suffer from AD and to maximize the likelihood of demonstrating a difference between drug and placebo when one exists [2]. Inclusion criteria generally identify a patient population of a specific disease severity. This is most often defined by a range of scores on the Mini-Mental State Examination (MMSE) [3]. Challenges in enrollment are not limited to trials of specific disease severities. As can be seen in the sample of published AD trials described in Table 1, examples of studies with fast rates of enrollment (for example, RR >1) exist for all disease severities. Similarly, slow enrollment can occur in trials in all stages of disease severity. Trials that fail to complete enrollment are also likely to go unpublished, given the probability that they will fail to meet the primary outcome [4]. To be clear, recruitment of participants with more severe disease faces unique challenges in comparison with studies of milder disease. Careful design and unique recruitment strategies, however, can be undertaken to overcome such challenges [5].

Besides disease severity, other specifications related to the population to be recruited can impact the rate of enrollment. For example, the Alzheimer's Disease Co-operative Study (ADCS) trial of estrogen replacement enrolled only women who had mild-to-moderate AD and who had undergone hysterectomy. Despite a somewhat wider range of MMSE inclusion criteria (12 to 28) than is typical, this trial enrolled only an average 10 subjects per month across 39 sites, and it took more than 3 years to complete enrollment [6].

Medication-related decisions

Criteria that exclude a large number of concomitant medications, though often necessary to ensure participant safety, can hinder recruitment. Many AD patients take supplements such as ginkgo biloba, and some trials exclude these patients. Alternatively, in trials examining available medications or supplements for therapeutic benefit in AD, the greater availability of these agents can pose a challenge to enrollment. The TRIMCI study of the anti-inflammatory agent trifusal in amnestic mild cognitive impairment (MCI) failed to meet its recruitment goals because of the high incidence of non-steroidal anti-inflammatory drug use among potential participants, which was exclusionary [7]. A recent trial of latrepirdine (formerly dimebon) excluded patients taking medications currently approved by the US Food and Drug Administration (FDA) for the treatment of AD. This study was conducted in part in the US, where there is a high prevalence of use of these prescription medications among those diagnosed with AD. The data related to recruitment for this trial are not yet available.

To increase the appeal to participants seeking new treatments, some studies incorporate alternate allocation, whereby randomly assigned participants have a greater chance of being assigned to an active treatment group than the placebo group. Although this may increase the appeal of participation to some patients, alternate allocation also requires increased sample size to maintain statistical power and it remains unclear whether this strategy abbreviates the total study recruitment period [8].

Design changes made after study initiation

Changes to study conduct after trial initiation but before the close of enrollment can impact recruitment. The original entry criteria for a phase III trial of tarenflurbil included mild-to-moderate AD patients with an MMSE score of between 15 and 26. Three months after enrollment began, the MMSE criteria for entry were changed to 20 to 26 as a result of findings from a phase II study [9]. Overall trial recruitment occurred from February 2005 until April 2008. Such changes mid-enrollment can counteract previous recruitment strategies. Similarly, stopping a study medication dose prior to closing enrollment is likely to impact recruitment. Dosing changes, especially those brought about by safety concerns, must be communicated to new participants as part of informed consent and may deter enrollment of new subjects. The high dose of the anti-amyloid antibody bapineuzumab was halted for safety reasons prior to closure of enrollment in a recent phase III study. Alternatively, the publication of positive data related to a study drug might improve enrollment. The same phase III study of bapineuzumab was still enrolling when data were published from phase II efficacy [10] and biomarker [11] trials. Data on the recruitment rates for the bapineuzumab phase III study are not yet available. Trials of drugs for which previous positive trials have been conducted are likely to enroll quickly. The initial trial of memantine in moderate-to- severe AD (MMSE 3 to 14) enrolled 252 subjects at 32 US sites over the course of 9 months [12] and demonstrated a significant difference from placebo on the primary efficacy outcomes. Consequently, a trial of memantine in moderate-to-severe AD (MMSE 5 to 14) patients taking donepezil efficiently enrolled 404 patients at 37 trial sites over the course of 6 months [13].

Barriers related to the Alzheimer's disease patient-caregiver dyad

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, 26–28]. Other motivations include desperation resulting from a lack of other treatment options [21, 26] and a desire to help medical science pursue a cure [21, 26, 27, 29, 30]. 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 [32–34]. They often cite the fear of side effects for the patient as a barrier to participation [21, 28]. 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.

What is the available pool of patients for Alzheimer's disease trials?

Many promising therapies are in clinical development for AD and more will enter clinical trials in coming years. To plan the recruitment of adequate subject populations for these trials, it will be necessary to better understand the pool of eligible patients qualified to participate. More than 400,000 Americans are diagnosed with AD annually [41]. Hence, investigators might assume that they have an ample (and growing) supply of participants for trials. Among all dementia patients, however, roughly half are moderately severe or more advanced in their disease [42, 43] and therefore fail to meet the mild-to-moderate category for which most trials currently recruit. The majority of all AD patients are older than 75 years [43], increasing the likelihood of exclusion for reasons such as comorbidities or prohibited medications. In fact, analyses of general clinical AD populations suggest that only 10% to 13% are eligible for clinical trials [44, 45]. In sum, the pool of eligible trial participants for AD trials is limited.

In 2009, at least seven phase III trials (of five drugs) recruiting in the US required a combined total of 8,510 participants (solanezumab [LY2062430] n = 1,000 [ClinicalTrials.gov ID NCT00905372] and n = 1,000 [NCT00904683]; semagecestat [LY450139] n = 1,100 [NCT00762411] and n = 1,700 [NCT01035138]; bapineuzumab n = 1,300 [NCT00574132] and n = 1,000 [NCT00575055]; dimebon n = 1,050 [NCT00829374]; and intravenous immunoglobulin n = 360 [NCT00818662] [1]). There were more, though smaller, phase II studies. Screening ratios are generally better than 2:1 (2 patients screened to enroll 1) (Table 1), but the fact remains that a significant number of patients recruited will not be enrolled. Thus, if one considers the newly diagnosed patients each year, the barriers to enrollment, and the number of participants needed as multiple trials are conducted simultaneously, it is clear that the recruitment needs for AD clinical trials will remain a challenge that results in competition for eligible subjects. Strategies to overcome the current barriers to recruitment must be developed.

How can trial recruitment be optimized?

The most straightforward approach to improving the rate of enrollment is to increase the number of trial sites. AD trials have become increasingly 'global', enrolling from multiple countries and continents within single studies. This change brings potential methodological [46] as well as ethical challenges when less industrialized nations are involved for which access to the drug (once it is approved) is not likely [47] (Declaration of Helsinki). Moreover, trial recruitment is difficult in all countries, not just the US [48]. It has been shown that, with increasing trial site number, the likelihood of placebo decline is reduced [49]. Furthermore, expanding the number of trial sites results in the inclusion of sites that are not focused on AD as a therapeutic area.

AD trials are optimally performed at trial sites experienced in their specific conduct by staffs well versed in the issues AD patients and their families face. Trials can be designed to facilitate participation for the subject and their study partner. Performing visits in the home and otherwise limiting travel hassles will increase the willing-ness to participate among caregivers.

Awareness of trials must be increased. Efforts to increase awareness should target both patients and caregivers. The fact that most caregivers are adult children but most study partners are spouses indicates that there remains a large number of uninformed or unwilling potential participant dyads. Social media may provide an avenue to specifically target adult children caregivers. The Wisconsin Registry for Alzheimer's Prevention has successfully enrolled more than 1,400 middle-aged adult children of AD patients in a natural history study [50], and the use of television advertising has been an effective means of recruitment. Similarly, web-based patient registries such as http://www.patientslikeme.com[51] have been used effectively in other therapeutic areas. Internet use among those over the age of 65 is increasing, and 'wired seniors' are likely to seek health-care information specifically when online [52]. AD models of registries have been proposed and could target MCI and mild-stage AD potential participants and caregivers and also potential participants in prevention trials, such as baby boomers [53].

The advantage of disseminating the message of the value of clinical trials is to diversify the reasons why people enroll. The more reasons a person has for being in a trial, the more likely he or she is to enroll and, over time, stay in a trial. As participants experience adverse events and the efforts of study visits, those participants whose reasons for enrollment include trust in the investigator and a desire to help others are more likely to stay in a trial than are patients whose sole motivation is benefit to their health. This is especially true in AD clinical trials in which, to date, therapeutic benefit has been elusive.

Effective methods to limit competition among trials, facilitate enrollment, and match eligible candidates with appropriate trials would improve recruitment and retention and result in a more rapid drug development. Agencies to fill such needs could have a major impact on clinical research. Such agencies, however, should be supported by federal and state governments, not for-profit entities, and would thus be free of private corporate interests.