FDA Issues Revised Draft Guidance for Drug Development in Early Alzheimer Disease


The FDA recently issued revised draft guidance to assist drug companies in developing treatments for early Alzheimer disease, focusing on diagnostic criteria, clinical staging, and outcome measures.

Teresa Buracchio, MD, director of the Center for Drug Evaluation and Research’s Office of Neuroscience

Teresa Buracchio, MD

Credit: LinkedIn

According to an announcement, the FDA has issued a revised draft guidance for industry leaders titled “Early Alzheimer's Disease: Developing Drugs for Treatment.” Once the guidance is finalized, the agency noted the information will help to provide recommendations for drug companies in development of treatments for patients in the early stages of Alzheimer disease (AD) that occur before the onset of overt dementia.1,2

This newly proposed draft guidance is a revision of the prior draft issued on February 16, 2018.3 The FDA noted in the statement that participants can submit either electronic or written comments on the draft until May 13, 2024, to ensure the agency considers the comment before the initiation of the final version.

“The FDA is committed to reducing the burden of AD,” Teresa Buracchio, MD, director of the Center for Drug Evaluation and Research’s Office of Neuroscience, said in a statement.1 “This guidance document provides the agency’s current thinking about diagnostic criteria and clinical staging and the selection of appropriate outcome measures, including the use of surrogate endpoints, for the early stages of AD.”

Top Clinical Takeaways

  • The FDA's revised guidance aims to streamline drug development for early-stage AD by focusing on diagnostic criteria and outcome measures.
  • Surrogate endpoints, like biomarkers, are suggested for use in clinical trials to predict clinical benefit in patients with early AD.
  • Drug developers are encouraged to engage with the FDA early in the development process regarding the use of surrogate endpoints for AD treatment trials.

READ MORE: FDA AdComm to Review Investigational Alzheimer Agent Donanemab and Phase 3 Results

In the statement, the FDA noted that this revision will reflect the agency's current perspective on the use of biomarkers for the selection of participants with early stages of AD for enrollment into clinical trials, the selection of outcome measures for clinical trials in early AD, and the utilization of effects on characteristic pathophysiological changes of AD to support approval in these patient populations. Notably, this draft revision is being issued consistent with the agency's good guidance practices regulation.

The agency also noted that participants can use an alternative approach if it complies with the requirements of the applicable statutes and regulations. Although this guidance has no collection of information, material does refer to previously approved FDA collections of information.

For patients in earlier stages of AD, drug developers may consider using surrogate end points, which can be a laboratory measurement, medical imaging, physical sign, or other assessment that is not an indication of clinical benefit but likely to predict it. The agency noted in a statement that drug developers considering the use of a surrogate end point as the primary measure of effect should discuss their plans with the agency during the early development process. Additionally, the FDA emphasized that it highly supports and encourages the continuation of research in understanding the role of surrogate end points and underscored their potential of importance for successful development of effective treatments in earliest stages of AD.

In a report on the revised 2018 FDA guidance for early AD, investigators revealed a significant shift in the importance to the meaningfulness of clinical outcome assessments (COAs) compared with the prior 2013 draft guidance.4 Published in The Journal of Prevention of Alzheimer's Disease, researchers noted that the implications of this update change included the assertion that cognition is clinically meaningful but a potent effect on cognition, depending on the disease stage, that is of enough magnitude and established across multiple relevant domains, can be supported by biomarkers reflecting underlying AD pathological changes.

The prior report, conducted by lead author Chris J. Edgar, PhD, executive scientific advisor at Cogstate, and colleagues, noted that meaningfulness is formed through understanding of the conceptual relevance of the assessed measurement and magnitude of treatment effects. In addition, authors noted that examples of this exist in previous FDA guidance and other publications for the way that meaningfulness can be assessed. Researchers underscored in the report that building upon conceptual models of AD and development of direct measures of meaningful health outcomes will significantly impact measurement of efficacy in clinical trials.

1. FDA issues guidance regarding drug development for early Alzheimer’s disease. News Release. U.S. Food and Drug Administration. Published March 11, 2024. Accessed March 14, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-guidance-regarding-drug-development-early-alzheimers-disease
2. U.S. Food and Drug Administration Early Alzheimer’s Disease: Developing Drugs for Treatment. Guidance Document. Published March 11, 2024. Accessed March 14, 2024.
3. U.S. Food and Drug Administration. Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry.; 2018.
4. Edgar CJ, Vradenburg G, Hassenstab J. The 2018 Revised FDA Guidance for Early Alzheimer's Disease: Establishing the Meaningfulness of Treatment Effects. J Prev Alzheimers Dis. 2019;6(4):223-227. doi:10.14283/jpad.2019.30
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