FDA Releases Much-Anticipated Guidance around Trial Endpoints

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The FDA released guidelines Thursday in an attempt to clarify processes for assessing a drug candidate’s efficacy while simultaneously examining several endpoints.

Having more than one principal measure for a candidate’s efficacy poses unique analytical problems, according to the FDA.

The document outlined the agency’s new process for interpreting the results of clinical trials that employ multiple primary endpoints.

For instance, a molecule that meets only one of a series of independent efficacy metrics could mistakenly be concluded as effective. Meanwhile, a compound that fails to impact a combination of several measures could be prematurely deemed ineffective.

“When more than one endpoint is analyzed in a single trial, the likelihood of making false conclusions about a drug’s effects with respect to one or more of those endpoints could increase if there is no appropriate adjustment for multiplicity,” the FDA wrote in the report.

Some diseases have more than one symptom or manifestation that are critical to their pathology, and employing a single efficacy endpoint wouldn’t accurately determine if a drug is effective. In these cases, the FDA would assess compounds using two or more independent metrics, which it calls co-primary endpoints, that must be satisfied.

Recent Wins and Losses Due to Multiple Endpoints

In its briefing document, the FDA gave migraines as an example, pointing out that while pain is indeed the condition’s defining symptom, several others—such as nausea and light sensitivity—are also clinically important.

In December 2021, migraine leader Biohaven Pharmaceutical cleared this co-primary endpoint bar in a Phase III study of its intranasal migraine hopeful zavegepant. The study, which enrolled 1,405 adult patients, assessed whether Biohaven’s candidate could hit two independent efficacy measures: pain freedom and freedom from the most bothersome symptom at two hours.

The FDA accepted Zavegepant’s new drug application in May.

The issue of proving efficacy on multiple fronts is what ultimately tripped up Biogen’s and Eisai’s Alzheimer’s disease drug Aduhelm (aducanumab).

Though it eventually received the FDA’s greenlight in June 2021, becoming the first-ever approved drug for Alzheimer’s disease, the drug has been marred by widespread skepticism and controversy.

The drug failed to make much traction in practical use. In April, after some 10 months of controversy, U.S. medical insurers strongly limited their reimbursement guidelines for Aduhelm, which crippled its uptake. A few months later, Biogen and Eisai abandoned a post-market observational study of the drug, citing low enrollment.

Aduhelm hit one efficacy endpoint, but didn’t conclusively do so for others.

“Many diseases have multiple sequelae, and an effect demonstrated on any one of these aspects could support a conclusion of effectiveness,” the FDA wrote in Thursday’s guidance document. “Selecting and focusing on just one of these sequelae is insufficient, while choosing many, while pathologically more appropriate, could be problematic.”