Public Citizen Demands Investigation into "Inappropriate Collaboration" Between FDA and Biogen Over Alzheimer's Drug
The consumer’s group Public Citizen demanded the Office of the Inspector General (OIG) for the U.S. Department of Health and Human Services (HHS) conduct an investigation into “inappropriate collaboration” between the U.S. Food and Drug Administration (FDA) and Biogen over the company’s submission for Alzheimer’s drug aducanumab.
In March 2019, Biogen and its collaboration partner, Tokyo-based Eisai, announced they were discontinuing the ENGAGE and EMERGE Phase III trials of aducanumab in patients with mild cognitive impairment from Alzheimer’s, as well as the EVOLVE Phase II trial and the long-term extension PRIME Phase Ib trial. An independent data monitoring committee indicated the trials were unlikely to hit their primary endpoints in a futility analysis.
Everyone thought aducanumab for Alzheimer’s was now dead, and likely taking the amyloid-theory of Alzheimer’s along with it. That theory is that accumulation of beta-amyloid in the brain is the cause of the cognitive and memory issues related to Alzheimer’s.
Then, in late October 2019, the companies indicated that after discussions with the FDA, and further analysis of the data, they were going to pursue regulatory approval for the drug. And in early December, Biogen presented full data on the drug at the 12th Clinical Trials on Alzheimer’s Disease (CATD) conference held in San Diego.
What they presented was that the Phase III EMERGE trial met its primary endpoint, showing a significant decrease in clinical decline. Biogen said the data from a subset of patients that received a high enough dose of the drug had significant benefits on measures of cognition and function, including memory, orientation, and language, as well as benefits on activities of daily living.
Although many had issues with some of the data, which was very complex, the companies felt they had a strong enough case to submit it to the FDA and were expected to do so this spring, which they did.
The submission was completed with ongoing collaboration with the FDA and include data from the Phase III EMERGE and ENGAGE trials, as well as the Phase Ib PRIME study. Biogen also requested Priority Review.
On November 6, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee met and essentially voted against recommending the drug, although there was some uncertainty in the voting on specific data questions. The committee voted 8 to 1 that the data from the EMERGE study was not enough to show efficacy and 7 to 0 that the PRIME study failed to show evidence of efficacy, and 5-0 that it presented strong evidence of the drug’s pharmacodynamic effect on Alzheimer’s. The agency has a PDUFA date of March 7, 2021, to decide on whether to approve the drug.
“There were clear cognitive benefits on a number of endpoint measures, which [is] unprecedented in a Phase III Alzheimer disease trial, and furthermore, there was a very clear indication of target engagements, as measured by a dose-dependent reduction in amyloid plaques on amyloid PET,” said Thomas Wisniewski, professor of neurology, and director, Pearl I. Barlow Center for Memory Evaluation and Treatment, who was not associated with the studies, told NeurologyLive. He added that the potential of the drug was “game-changing” and even though the effect size was not large, “it does look like it’s disease-modifying and of cognitive benefit.”
It is unlikely aducanumab would have made it this far if there were any effective treatments for Alzheimer’s disease, which is a disease with an increasingly growing older population and a largely unmet medical need. But Alzheimer’s drug development has been a wasteland of failed mid- and late-stage clinical trials, and there is a feeling of increasing desperation for any drug that might prove to be even a little effective.
In the adcom meeting, several committee members criticized FDA’s briefing notes, accusing the agency of demonstrating “bias” towards the therapy and Biogen and “discordance” between the FDA’s clinical and statistical reviewer.
“Standards need to be kept as high as established,” said Leon Henderson-MacLennan, medical advisor at inThought Research. He added, “This [vote] will make it more difficult, although not impossible, of course, for the agency to ignore this strong no-confidence stance.” If the agency does eventually approve aducanumab, he said, it would represent the agency “going over the heads of the entire neuro leadership.”
Advisory committee votes are non-binding. The agency typically follows the committee recommendations, but not always.