FDA Sets Date for Eli Lilly’s Donanemab Adcomm While Pondering Changes to Format

The date for this year’s most-anticipated advisory committee meeting has been announced. The FDA will convene its Peripheral and Central Nervous System Drugs Advisory Committee on June 10, 2024, to discuss the New Drug Application for Eli Lilly’s Alzheimer’s drug donanemab.

The meeting will be held in person and focus on data from the Phase III TRAILBLAZER-ALZ 2 study, which enrolled 1,736 participants 60-85 years of age with early symptomatic disease. Trial participants with low to medium tau levels saw their cognitive decline decrease by 35% on the Integrated Alzheimer’s Disease Rating Scale (iADRS) and 36% on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) compared to placebo. Lilly had sought accelerated approval for donanemab but was denied in January 2023, mainly due to the design of the Phase II TRAILBLAZER-ALZ trial.

Original Article Published May 6:

On April 29, the FDA announced it would hold a listening session to discuss the composition of advisory committees and ways to ensure public awareness and understanding of their role in the regulatory process. The news comes as the agency gears up for arguably the biggest advisory committee meeting of the year, regarding Eli Lilly’s highly anticipated Alzheimer’s drug donanemab.

In March, Lilly announced that the FDA plans to convene an advisory committee (adcomm) before rendering a decision on donanemab. With FDA leaders embroiled in a debate about the format of such meetings, the layout of this one remains to be seen—including whether committee members will vote for or against approval as usual.

In January 2023, the FDA denied accelerated approval of donanemab, due mostly to the design of the Phase II TRAILBLAZER-ALZ trial. After releasing positive data from the Phase III TRAILBLAZER-ALZ 2 study in May 2023, the company filed for traditional approval and expected a decision by the end of last year. When that did not come to pass, Lilly advised that a decision was expected by the end of the first quarter of 2024. And here we are.

Adcomms regarding new drug approvals have traditionally consisted of hours of discussion followed by a vote and rationale provided by each committee member. But last year, FDA Commissioner Robert Califf appeared to advocate for eliminating the vote.

Joseph Ross, a professor of medicine and public health at Yale School of Medicine, is staunchly in favor of retaining the vote. “I think there’s a substantial amount of value to the discussion that takes place at the meeting, but I don’t think it’s at the expense of voting,” he told BioSpace. “I think both are equally important.”

At Eli Lilly, Dawn Brooks, global development leader for donanemab, told BioSpace the company is “actively preparing” for the summer meeting.

In the Phase II TRAILBLAZER-ALZ trial, patients were allowed to end treatment when amyloid plaques had been cleared past a certain pre-defined level, meaning fewer than 100 patients were on the drug for 12 continuous months. The FDA requested in its Complete Response Letter denying accelerated approval that the company supply data on at least 100 patients who had reached that milestone. In Phase III, treatment with donanemab significantly slowed cognitive and functional decline, Lilly reported in May 2023.

While Lilly said in March that it was “unusual” for the FDA to call for an adcomm this late in the regulatory process, some medical ethicists are in favor of the move. Ross said he believes it is “always best for the FDA to leverage this opportunity to get expert advice if there’s some larger controversy at stake or some other larger uncertainty that has relevance to public health.” He added that the FDA’s call for a donanemab adcomm “suggests that there’s evidence that bears discussion” and said he applauded the agency’s “decision to provide the public opportunity for input before they make a final decision.”

In June 2021, the FDA approved Aduhelm as the first new Alzheimer’s drug in nearly 20 years, going against the overwhelmingly negative vote of its Peripheral and Central Nervous System Drugs Advisory Committee. The decision set off a firestorm of backlash, including three committee member resignations. “[That situation] obviously didn’t go well from the perspective of the FDA,” Ross said.

Two studies—one led by Ross, the other by Harvard’s Aaron S. Kesselheim—have shown that the FDA follows the recommendations of its advisory committees more than 75% of the time. But the regulator doesn’t always call an adcomm to help it make its decisions, and the second study showed that between 2010 and 2021, the FDA “sought independent expert advice less frequently over time.”

This study also found that an initial approval for a product followed a positive vote 97% of the time, while non-approvals followed negative votes only 67% of the time. “There definitely is what I might call a pro-approval bias in their actions,” said Genevieve Kanter, an associate professor at the University of Southern California’s Price School of Public Policy.

Brooks said she expects the discussion at the donanemab adcomm to focus on overall safety and the benefit-risk profile both for individual subgroups and the broader Alzheimer’s population. Lilly’s clinical trials were designed to allow participants to stop active treatment once their plaques were cleared. Therefore, the company also expects discussion around how to capture this treatment protocol in the label, “particularly when what we have seen is generally the FDA has wanted to have consistency . . . between class labels,” Brooks said.

John Sims, head of medical-donanemab at Lilly, agreed that donanemab’s unique trial design “throws a few wrenches” into the agency’s aim for consistency across Alzheimer’s treatments. If donanemab’s trials were “rinse, wash and repeat, it would pose less questions and less uncertainties as how to kind of resolve these things,” he told BioSpace.

At the 2023 Biopharma Congress meeting, Califf advocated for “more comprehensive discussion” around products under review and said adcomm meetings should be “less about the outcome,” according to Regulatory Focus. But at this year’s meeting, Peter Stein, director of CDER’s Office of New Drugs, and Richard Pazdur, director of the Oncology Center of Excellence, argued in favor of retaining it, the outlet reported.

The impetus for Califf’s comments may well have been the Aduhelm debacle. In 2023 he noted, “The purpose of the advisory committee is not to produce gladiator votes, so people say the FDA does not agree with its advisory committees. The purpose is to get advice, and the best advice is not whether this drug should be approved. That decision should be made by full-time civil servants.”

In an email to BioSpace, an FDA representative reiterated this last point, saying that while insight from the expert panelists is valuable and taken into consideration, “final decisions are made by FDA career staff.”

Kanter told BioSpace she agrees there shouldn’t be as much focus on the concordance of adcomm recommendations and agency action. “The law states that it’s the agency that makes the final decision,” she said. However, she called the timing of the proposal “odd.”

“Usually, when we see a big procedural change—and this is a big one—it’s to solve a big problem. What’s kind of odd about this is there haven’t been any issues raised about voting or how advisory committees are run; not from the agency itself, not from advisory committee members, not from the public or the media,” she said. “So it’s a mystery to me . . . as to what problem this is trying to solve.”

Kanter said she believes the proposed change is “more related to managing public expectations rather than some fundamental problem with advisory committees, procedures and how they’re conducted.”

Kanter noted that divergence between an advisory committee’s recommendation and an FDA decision can occur due to a number of factors. “It might require explanation from the agency as to whatever additional considerations they’re including, and they may be limited in their ability to disclose some of those considerations because of laws regarding proprietary information.”

While Kanter said adcomms add transparency to the regulatory process for the public, she added that “it might be helpful for the agency to maybe be more explicit” about the specific goals of each meeting.

Ross said he would like to have a “better understanding of what triggers an advisory committee meeting, essentially the rationale for convening it. Perhaps that can be made better public.”

On the voting question, Ross said it will “be interesting to see where the agency arrives.” He noted, however, that as each new drug division makes its own decisions on advisory committees, there will be some flexibility for those who wish to continue to use votes.

For Lilly, Brooks said she doesn’t know if any potential format modification “will catch” donanemab, “but we’ll take it as it comes.”

Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.