Aduhelm Approval Under Review: HHS Watchdog Investigates FDA Pathway

HHS to Review FDA’s Accelerated Approval Pathway

The Office of the Inspector General (OIG) within the Department of Health and Human Services (HHS) has announced a comprehensive review of the Food and Drug Administration’s (FDA) accelerated approval pathway. This assessment was initiated following the contentious approval of Biogen’s Alzheimer’s medication, Aduhelm, just two months prior.

Understanding the Accelerated Approval Pathway

The FDA’s accelerated approval pathway is designed to expedite the availability of treatments for serious conditions where no adequate therapies currently exist. Drugs utilizing this pathway are approved based on achieving specific, preliminary indicators of benefit – known as surrogate endpoints.

Clinical benefit isn’t definitively proven at the time of approval, but is expected to be demonstrated through a subsequent phase four study.

The Aduhelm Controversy

This pathway was central to the approval of Aduhelm, the first new Alzheimer’s drug authorized since 2003. Concerns surrounding this decision prompted the HHS-OIG review, as detailed in the Inspector General’s announcement.

The approval of Aduhelm sparked debate due to perceived disagreements among FDA scientists, a negative recommendation from the advisory committee, and allegations of undue closeness between the FDA and Biogen. The use of the accelerated approval pathway itself was also questioned.

Questions Regarding Aduhelm’s Efficacy

Aduhelm, also known as aducanumab, was shown to reduce amyloid plaques in the brain, which are believed to disrupt neuronal communication. However, the extent to which this reduction translated into tangible benefits for patients remained uncertain.

Specifically, it was unclear if lowering amyloid plaque levels would effectively slow the progression of Alzheimer’s disease’s most debilitating symptom: cognitive decline.

Clinical Trial Results and Committee Recommendations

Phase three trials of Aduhelm were initially halted in March 2019 after independent monitoring committees determined the drug wasn’t improving cognitive decline rates.

A subsequent Biogen analysis in October revealed differing results; one trial showed no cognitive improvements, while the other indicated modest effects in patients receiving the highest doses.

Despite an independent FDA committee declining to endorse the drug in November 2020, Aduhelm received approval in June 2021.

Industry Reaction and Resignations

The approval initially fueled optimism within the pharmaceutical industry regarding potential for more biomarker-based approvals. However, this sentiment wasn’t universally shared within the scientific community.

Three members of the advisory committee resigned in protest, citing concerns about the inconsistent data. Major hospital systems, including Mt. Sinai and the Cleveland Clinic, indicated they would not prescribe the drug.

Allegations of Close Ties Between FDA and Biogen

Concerns arose regarding a potentially overly close relationship between the FDA and Biogen during the drug’s development and review process. Reports indicated Biogen launched “Project Onyx” to influence regulators, with some FDA officials actively participating in the drug’s approval process.

Acting FDA Commissioner Janet Woodcock requested an external review by the HHS-OIG in a July 9 letter to investigate this relationship.

“We believe an independent assessment is the best manner in which to determine whether any interactions that occurred between the manufacturer and the agency’s review staff were inconsistent with FDA’s policies and procedures,” Woodcock stated.

Scope of the HHS-OIG Investigation

The HHS-OIG investigation will not re-evaluate the scientific evidence supporting Aduhelm’s approval. Instead, it will focus on the entire accelerated approval pathway, assessing how and when the FDA permits drugmakers to utilize it.

The review will encompass interactions between the FDA and external entities, existing policies and procedures, and the FDA’s adherence to those procedures. It will examine the Aduhelm review process alongside other drugs approved through this pathway.

FDA Cooperation and Potential Ramifications

The FDA has pledged full cooperation with the HHS-OIG review. Any recommendations resulting from the investigation will be promptly evaluated and addressed.

Potential actions could significantly impact future drug approvals, particularly for companies developing Alzheimer’s treatments.

Impact on Other Alzheimer’s Drug Development

Eli Lilly is currently developing donanemab, another Alzheimer’s drug, and has presented preliminary findings indicating it lowers amyloid and other biomarkers, with associated patient improvements.

Eli Lilly’s senior vice president, Daniel M. Skovronsky, stated that the Aduhelm approval “reflects a shift in policy” and the company intends to seek accelerated approval for donanemab by year-end.

However, this pathway is now under scrutiny by the HHS-OIG.