Current Edition

Design and Conduct of Trials in Alzheimer’s
Disease Following the Impending Approvals
of Disease-Modifying Agents

Fortunately, after nearly two decades of negative studies, two amyloid-lowering drugs have recently received accelerated approval for Alzheimer’s Disease (AD) by the FDA, and one of these drugs is likely to receive full approval by July of this year. Submissions have also been made to regulatory authorities in Asia and Europe, and it is possible there will be global approval by the end of 2023, or early 2024. Notably, these drugs go beyond symptom management and appear to directly affect the disease pathology. Given the long dearth of new approvals and the shift from symptomatic treatment to disease modification, the clinical trial landscape will need to undergo substantial change when one or more of these drugs receives full approval. To aid sponsors and other stakeholders to navigate this new potential environment with success, several concepts and considerations are reviewed here.

Recruitment & Retention

While the regulatory authorities deliberate on the disease modifying therapies (DMT) in consideration for approval, research sites continue to try to recruit patients to ongoing AD clinical trials. Recruitment into study protocols in the more severe stages of the disease is less likely to be affected by these approvals, although the expected large influx of enquiries for treatment with one of the DMTs is bound to result in a resource issue at many trial sites, in terms of staffing. The real challenge for research sites will be the continued recruitment into DMT protocols in the Early AD (eAD) space. In the US, patients and families might prefer to wait for full approval by the FDA, rather than commit themselves to a long-duration, placebo-controlled trial with no guarantee of success, or an unknown safety profile. The Centers for Medicare and Medicaid Services (CMS) have intimated that if a monoclonal antibody directed against amyloid for the treatment of Alzheimer’s disease subsequently receives traditional FDA approval, CMS will provide broader coverage of reimbursement. Theoretically, at least in the US, this would mean that those patients with appropriate health insurance coverage would have their costs for treatment partially or fully reimbursed, although this of course needs to be confirmed. It is less clear, at this moment in time, whether the national or private health systems of countries outside the US will allow the reimbursement of the DMT upon approval from the applicable health/drug authorities.

Assuming that at least one DMT receives full approval, and CMS (or the corresponding national health system in other countries) agrees on a reimbursement package, typical eAD patients and caregivers will infer that approval confirms efficacy and a reasonable safety profile, while providers understand that all investigational compounds come with uncertainty on both fronts. Sponsors will need to give significant thought to educational programs and materials to equip site personnel to understand differences between the proposed investigational compound and approved treatments in the same space. This knowledge is critical for two reasons: 1) to speak to potential reasons to consider an investigational compound over an approved treatment, and 2) to ensure that site staff form educated opinions on the relative merits of treatment options for their patients.