The regulator’s new draft guidance, released on Monday, provides additional details regarding the use of surrogate and biomarker endpoints to support accelerated approvals.
Pictured: Facade of the FDA’s office in Maryland/iStock, Grandbrothers
The FDA on Monday published a revised draft guidance document, aimed at helping sponsors and pharmaceutical companies to develop therapies for Alzheimer’s disease, particularly in its early stages before the onset of overt dementia.
Monday’s draft document updates the FDA’s previous guidance, released in February 2018. The regulator’s guidance is generally non-binding and not legally enforceable; instead, it describes “the Agency’s current thinking on a topic and should be viewed only as recommendations.”
Compared with the 2018 document, the latest version of the FDA’s draft guidance has been substantially changed, as the regulator introduced a new subsection dedicated specifically to surrogate endpoints and accelerated approval.
The FDA’s guidelines now explicitly provide for the use of biomarker data, such as brain amyloid beta burden, to support the accelerated approval of Alzheimer’s disease (AD) therapies. The regulator emphasized that these surrogate endpoints should be “reasonably likely to predict clinical benefit,” and that companies are still required to run post-approval trials to validate the clinical efficacy of their product.
The FDA also noted that the acceptability of surrogates depends on various factors, including the stage of AD, the availability of current treatments, the study population and the mechanism of action of the investigational therapeutic.
“A surrogate endpoint that is determined to be appropriate for use in a particular therapeutic clinical development program should not be assumed to be appropriate for use with a different product or trial population,” the FDA wrote in its updated draft guidance, adding that companies considering hinging their applications on biomarker data “should discuss their plans with FDA early in development.”
The regulator also noted that even if companies are aiming for accelerated approval, they should still include clinical outcome data in their applications, which would “potentially provide support for any changes observed on biomarkers.”
The FDA’s updated draft guidance comes as it pushed back its target action date for Eli Lilly’s investigational antibody donanemab. Last week, the regulator informed Lilly that it would convene its Peripheral and Central Nervous System Drugs (PCNS) Advisory Committee to discuss the pharma’s TRAILBLAZER-ALZ 2 study, focusing on its “unique trial design” and its potential implications on efficacy and safety findings.
TRAILBLAZER-ALZ 2 is a Phase III, double-blinded and placebo-controlled study with more than 1,700 participants. For enrollment, Lilly selected patients using cognitive assessments and brain imaging studies to assess their amyloid plaque and tau concentrations. The study also had a unique dosing protocol that allowed patients to stop treatment if amyloid plaques dropped beyond a certain pre-specified threshold.
In January 2023, this study design led to the FDA’s rejection of donanemab’s bid for accelerated approval.
Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.
