Key Takeaways from FDA Draft Guidance on Amyotrophic Lateral Sclerosis


There are significant unmet clinical needs among patients with amyotrophic lateral sclerosis.

The FDA recently released a draft guidance intended to bolster drug development for the treatment of amyotrophic lateral sclerosis (ALS). The goal of the document is to help sponsors develop novel treatments for the neurodegenerative disease.

The draft guidance discusses the clinical development of treatments that can address the neuromuscular effects of ALS, including muscle weakness and difficulty in swallowing, breathing, and speaking; however, the FDA noted that the guidance does not outline strategies for developing drugs that treat other ALS-related symptoms.

For early phase clinical trials, the FDA advises researchers that intrathecal delivery may be necessary for these treatments. Typically, early studies can feature a single-dose injection, but sponsors should consider drug-device co-development if long-term delivery is being pursued, according to the document.

These trials should enroll patients who meet the current diagnostic criteria and can include identified patient subgroups of ALS variants when necessary.

The FDA advises sponsors to establish the efficacy of an investigational ALS drug by demonstrating clinically meaningful effects on symptoms or survival improvements. Trials should also include measurements of mortality effects that can contribute to the overall safety and efficacy profile of novel treatments.

ALS clinical trials should also be conducted with oversight from a data monitoring committee that looks for safety signals and takes appropriate action to prevent patient harm, according to the document.

The FDA warns that a high percentage of patients with ALS will experience serious adverse events or death during the trial, especially in longer-term studies. These effects should be analyzed to determine whether they were the result of the disease or the treatment, according to the document.

To gain approval, drug safety should be supported by a group of patient exposures and responses to ensure that the risks are properly characterized.

The FDA also advised that sponsors should design randomized, placebo-controlled, double-blind clinical trials, according to the document. Studies may also be designed as add-on or dose-response for investigational ALS drugs.

Significantly, the agency plans to consider the proposal of new outcome measures that encapsulate the clinically meaningful effects of the drug, as existing measures may not be appropriate for ALS, according to the document.

The efficacy of an ALS therapy can be demonstrated through benefits in day-to-day function and survival, including the need for respiratory support. These endpoints should be controlled for biases because they can rely on patient reporting and patient motivation, according to the FDA.

Additionally, functional endpoints can be affected by patient deaths, but using an analytical approach that accounts for survival and function into a single measure may mitigate issues, according to the document.

Due to the significant progression of ALS, establishing a clinical benefit—even if it is modest—can result in an approval consideration, the FDA reported.

“In the future, greater scientific understanding of ALS may provide opportunities for discussion of surrogate endpoints that are reasonably likely to predict clinical benefit and that might serve as a basis for accelerated approval,” the FDA wrote.

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