2021: Aducanumab: Controversial Alzheimer's Approval (2021)

The FDA's accelerated approval of aducanumab (Aduhelm, Biogen) on 7 June 2021 for Alzheimer's
disease became one of the most controversial regulatory decisions in the agency's modern history,
generating intense debate about the accelerated approval pathway, the surrogate endpoint of amyloid
reduction, and the relationship between biomarker change and clinical benefit. Aducanumab is a
human monoclonal antibody targeting aggregated amyloid-beta, particularly high-molecular-weight
oligomers and protofibrils, designed to promote clearance of amyloid plaques from the brain.

The drug's clinical development was turbulent. Two Phase III trials (EMERGE and ENGAGE) were
halted in March 2019 following an interim futility analysis. Biogen's subsequent re-analysis,
using a larger subset of data from patients who received the high dose for a longer period, claimed
that EMERGE showed a 22 % slowing of clinical decline while ENGAGE did not. The FDA's own advisory
committee voted 10-0-1 against approval, concluding that the evidence did not support clinical
benefit. The FDA overruled this recommendation and granted accelerated approval based on
aducanumab's ability to reduce amyloid plaques as a surrogate endpoint—requiring a confirmatory
post-marketing trial.

Three FDA advisory committee members subsequently resigned in protest. Medicare declined to provide
broad coverage, limiting reimbursement to patients enrolled in approved clinical trials. The drug
was launched at $56,000 per year—later reduced to $28,200—but uptake was minimal. In January 2024,
Biogen and Eisai discontinued aducanumab's commercial development, withdrawing it from the US market.

Despite its commercial failure, aducanumab's approval provoked valuable regulatory and scientific
debate about surrogate endpoints in neurodegeneration and indirectly shaped the regulatory strategy
for the subsequent anti-amyloid antibodies lecanemab and donanemab.