Eli Lilly Prepares for Donanemab Adcomm Amid FDA Format Changes

On April 29, the FDA announced a forthcoming listening session aimed at discussing the composition of its advisory committees and how to ensure public awareness and understanding of their roles in the regulatory process. This session is particularly timely as the FDA prepares for a major advisory committee meeting to evaluate Eli Lilly's anticipated Alzheimer’s drug, donanemab.

In March, Eli Lilly revealed that the FDA would convene an advisory committee before making a decision on donanemab. This announcement followed the FDA’s January 2023 decision to deny accelerated approval of the drug, primarily due to the design of the Phase II TRAILBLAZER-ALZ trial. Following positive results from the Phase III TRAILBLAZER-ALZ 2 study released in May 2023, Lilly sought traditional approval, anticipating a decision by late 2023. However, when that decision was not reached, the company advised that a decision was expected by the end of the first quarter of 2024.

The structure of these advisory committee meetings has been a point of discussion. Traditionally, such meetings involve hours of deliberation followed by a vote and individual rationales from committee members. However, FDA Commissioner Robert Califf has suggested potentially eliminating the vote component, a move that has sparked debate. Joseph Ross, a Yale School of Medicine professor, advocates for retaining the vote, emphasizing the value of both the discussion and the voting processes.

Eli Lilly’s global development leader for donanemab, Dawn Brooks, mentioned that the company is actively preparing for the advisory committee meeting. The Phase II trial allowed patients to end treatment once amyloid plaques were cleared to a pre-defined level, leading to fewer than 100 patients being on the drug for 12 continuous months. The FDA requested data on at least 100 patients who had reached this milestone before considering accelerated approval. In the Phase III trial, donanemab showed significant slowing of cognitive and functional decline.

While it is unusual for the FDA to call for an advisory committee meeting at this stage in the regulatory process, some medical ethicists support the decision. Ross believes it is beneficial for the FDA to seek expert advice when significant controversy or uncertainty exists. He praised the agency’s decision to involve public input before finalizing their decision on donanemab.

The background of this discussion includes the FDA’s controversial approval of Aduhelm in June 2021, the first new Alzheimer’s drug in nearly two decades, which went against the negative vote of its advisory committee. This decision led to significant backlash and resignations from three committee members.

Studies by Ross and Harvard’s Aaron S. Kesselheim indicate that the FDA follows advisory committee recommendations more than 75% of the time. However, the frequency of convening such committees has decreased over time. One study found that initial approvals following a positive vote occurred 97% of the time, whereas negative votes led to non-approvals only 67% of the time, indicating a possible pro-approval bias.

Brooks expects the donanemab advisory committee discussion to focus on the drug’s overall safety and the benefit-risk profile for individual subgroups and the broader Alzheimer's population. John Sims, head of medical-donanemab at Lilly, acknowledged that the unique trial design of donanemab poses challenges to the FDA’s aim for consistency across Alzheimer’s treatments.

At the 2023 Biopharma Congress meeting, Califf advocated for more comprehensive discussions around products under review, with less emphasis on the outcome. However, other FDA officials, including Peter Stein and Richard Pazdur, argued in favor of retaining the voting process.

The impetus for Califf’s comments may have been the Aduhelm incident, where the FDA approved the drug despite negative advisory committee votes. An FDA representative reiterated that final decisions are made by FDA career staff, although input from advisory committees is valuable.

Genevieve Kanter from the University of Southern California’s Price School of Public Policy suggested that the proposed changes might aim to manage public expectations rather than address fundamental issues with the advisory committee process. She emphasized the need for greater transparency regarding the rationale for convening advisory committee meetings and the specific goals of each meeting.

Ross expressed a desire for a clearer understanding of what prompts an advisory committee meeting and noted that flexibility exists for individual drug divisions to continue using votes if they choose. Brooks stated that Eli Lilly would adapt to any changes in the advisory committee format as they occur.