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New FDA Draft Guidance Focuses on Biomarker Use in Early Alzheimer's Drug Development

NEW YORK – The US Food and Drug Administration on Monday issued an updated draft guidance for drugmakers developing treatments for early-stage Alzheimer's disease.

The new version updates a previous draft the FDA released in 2018 and is designed to support sponsors as they develop drugs for patients with early signs of the neurodegenerative disease, but before the onset of overt dementia. While similar to the 2018 version, the updated draft includes a sharper focus on the accelerated approval pathway and information on biomarkers that have been used as the basis for the approval of such drugs since the last guidance.

Recommendations that the FDA makes in guidance documents aren't legally binding but represent the agency's current thinking on how sponsors can best meet regulatory expectations.

For instance, in its new recommendations on outcome measures in the updated draft, the FDA suggested that sponsors include both clinical outcome assessments and biomarkers in clinical trials of patients with early Alzheimer's. But the appropriate approval pathway will differ based on the type of primary endpoint sponsors select, the agency noted.

"Direct measures of clinical benefit or validated surrogate endpoints may support a traditional approval," the FDA wrote. "Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical benefit but that are considered reasonably likely to predict clinical benefit may support an accelerated approval."

Two drugs designed to slow progression of early Alzheimer's have received accelerated approval from the FDA: Biogen and Eisai's Aduhelm (aducanumab-avwa), which is being discontinued after its controversial approval and slow sales, and Leqembi (lecanemab-irmb), which was later converted to a full approval based on results from a confirmatory trial.

Both drugs initially received accelerated approval based on their ability to clear beta-amyloid plaque in the brain, a hallmark sign of Alzheimer's.

However, the FDA stressed that just because a surrogate endpoint is used as the basis for accelerated approval in one trial doesn't mean it's appropriate for all studies of early Alzheimer's — an appropriate surrogate endpoint will depend on the disease stage, population enrolled in trials, therapeutic mechanism of action, and availability of existing treatments.

"Sponsors considering the use of a biomarker as the primary measure of effect should discuss their plans with FDA early in development," the agency wrote in a new section in the updated guidance on surrogate endpoints. "FDA strongly supports and encourages continued research in understanding the role of biomarkers in AD and stresses the potential importance of biomarkers in the successful development of effective treatments appropriate for use in the earliest stages of AD."

The draft guidance characterizes three stages of early Alzheimer's based on pathophysiological changes and the identification of subtle cognitive or functional issues, which the agency said it hopes will inform development of clinical trials that enroll patients at earlier stages of disease and potentially delay, halt, or even reverse disease progression and avoid advancement into dementia. The FDA said, "characteristic pathophysiological changes are typically demonstrated by assessment of various biomarker measures," but did not specify what biomarkers to use.

"Historically, clinical criteria that defined later stages of AD, after the onset of overt dementia, were used for enrollment in clinical trials," the agency wrote. "Accordingly, subjects included in these trials exhibited both the cognitive changes typical of clinically evident AD and the degree of functional impairment associated with overt dementia."

The FDA said sponsors should use the three early disease stages to define the study population and guide their selection of outcome measures. Biomarkers will likely play a critical role in reviewing treatments for early Alzheimer's, the FDA said, as it can take years for sponsors to establish a clinically meaningful treatment effect in this population given that patients in question have no or minimal cognitive or functional impairments — making it challenging to find an appropriate outcome to compare patients on before and after treatment. The FDA said it intends to consider outcomes measures, including cognitive assessments and surrogate endpoints, to facilitate shorter trials.

In cases where biomarker evidence is needed to define the study population, but no diagnostic tests are available, the FDA said sponsors should discuss potential need for development of a companion diagnostic device with the agency early on.

The FDA is seeking industry feedback on the draft guidance through June 10 to inform a finalized version.