Mitigating barriers to recruitment and retention in early stage Alzheimer’s trials

By Peter Schueler

Despite recent approvals of treatments for early Alzheimer’s disease, therapeutic development continues to be hampered by challenges with patient recruitment and retention. This long-standing challenge is even more pronounced for Alzheimer’s trials that aim to recruit patients in the early stages of the disease when clinically recognisable symptoms are often absent.

Instead, identifying early-stage individuals necessitates biomarker-based screening, which adds layers of complexity to an already-challenging recruitment process. Moreover, recent efforts to enrol more representative patient populations in Alzheimer’s clinical trials have been confounded by biomarker-based inclusion criteria, such as amyloid positivity, which can disproportionately exclude certain racial groups.

Overall, the recruitment and retention of qualified, heterogeneous patient populations was reported to be the top central nervous system (CNS) clinical development challenge, according to an ICON survey of over 120 neurodegenerative therapeutic developers.  Accelerating the development of effective therapies for Alzheimer’s disease will depend on sponsors’ ability to successfully mitigate barriers to recruitment and retention that are particularly challenging for early-stage Alzheimer’s trials.

As evidenced by many of today’s ongoing early intervention trials – such as the AHEAD 3-45 study – these approaches include:

1. Implementing inclusive enrolment strategies
2. Proactively identifying and characterising trial-ready individuals
3. Trial designs that mitigate patient burdens.

Adjustments to clinical trial design, particularly the examination of inclusion criteria, are essential for accelerating the enrolment of underserved patient populations. Traditional inclusion criteria in Alzheimer’s have excluded people with medical conditions that are more prevalent in underserved populations.

Additionally, lower average amyloid levels in black individuals have reduced their eligibility for some Alzheimer’s clinical trials with biomarker-based inclusion criteria. Ensuring that inclusion criteria demonstrate consistency across patient populations may, therefore, help to streamline and accelerate diverse enrolment. This includes the adoption of biomarkers, such as the ratio of plasma Aβ42/40, which have demonstrated more consistency across racial groups.

The evaluation of inclusion criteria may be one element of a more holistic plan for representative populations, which provides a roadmap for more inclusive enrolment and retention, including strategies for direct engagement, education and relationship building with historically underrepresented populations. However, only about one in four developers in the ICON survey (26%) reported using such plans during clinical development.

Identifying and characterising trial-ready individuals streamlines clinical trial enrolment and accelerates the recruitment of qualified patients, particularly for early-stage diseases or trials with biomarker-based eligibility. Despite this, less than a third (32%) of CNS developers reported using registries and non-interventional trials, which can proactively identify eligible individuals using a combination of remote recruitment and targeted biomarker screening. As an alternative to registries, developers can also implement stepwise patient screening approaches that use less resource-intensive methods – such as medical record reviews and blood-based biomarkers – to help identify individuals who are more likely to meet eligibility criteria.

Decentralised or hybrid trial methods, reportedly adopted by only 29% of survey respondents, can improve patient recruitment and retention by alleviating many of the challenges associated with on-site clinical trial participation. Conducting all or part of a trial in the patient’s home is especially impactful for patients with neurodegenerative conditions, who disproportionately have mobility issues, travel constraints or preferences to remain in familiar places. It also reduces the financial, logistical and emotional burden on these patients and their caregivers. Implementing in-home health visits and a decentralised model has been key to the largest randomised clinical trial ever conducted on Parkinson’s disease, which plans to enrol over 3,500 patients.

Reducing the likelihood that an individual patient will be assigned to a placebo arm in a clinical trial can also incentivise enrolment. One way to achieve this is through master protocol designs, including umbrella, basket and platform trials, which allow for the efficient evaluation of multiple therapies or diseases simultaneously, while requiring only one control group.

Another option for reducing the number of placebo-arm participants is through the implementation of historic controls. These can be utilised in certain situations, particularly in early-stage research or rare diseases, to reduce the need for concurrent control arms, potentially expediting enrolment. However, these approaches are infrequently used, with less than a quarter of respondents reported using historic controls (22%) or platform trial designs (19%).

Learn more about accelerating the development of early stage Alzheimer’s treatments with innovative trial designs in ICON’s white paper and survey report.