The Department of Health and Human Services (HHS) Office of the Inspector General will review the FDA’s accelerated approval pathway, the office announced Wednesday. This sweeping review comes just two months after the controversial approval of Biogen’s Alzheimer’s drug Aduhelm.

The review will focus on the FDA’s accelerated approval pathway — a route that allows drugs for serious diseases without existing treatments to be approved if they hit certain interim benchmarks (called surrogate endpoints). These drugs are thought to provide clinical benefit, but that benefit hasn’t actually been demonstrated before the drug is approved. Once the drug is approved, a phase four study would need to demonstrate clinical efficacy.

This is the pathway that allowed for the highly controversial approval of Aduhelm, the first Alzheimer’s drug to be approved since 2003. It’s this approval that set the HHS-OIG review process in motion, per the Inspector General’s Wednesday announcement.

“The FDA’s approval of Aduhelm raised concerns due to alleged scientific disputes within the FDA, the advisory committee’s vote against approval, allegations of an inappropriately close relationship between the FDA and the industry, and the FDA’s use of the accelerated approval pathway,” the announcement reads.

“In response to these concerns, we will assess how the FDA implements the accelerated approval pathway.”

While the FDA has defended its decision to approve Aduhlem via this pathway, there has been significant backlash about the drug’s efficacy and how it got approved in the first place.

Aduhelm, also known as aducanumab, had demonstrated it could reduce amyloid plaques in the brain (sticky compounds that disrupt communications between brain cells). However, there have been lingering questions about how much patients actually benefited from the drug. It was unclear whether lowering levels of amyloid plaques would actually slow rates of Alzheimer’s most pernicious symptom: cognitive decline.

In March 2019, two phase three trials of the drug were shut down after independent monitoring committees found that the drug wasn’t improving patients rates of cognitive decline. Another analysis conducted by Biogen in October, however, yielded different results. One phase three clinical trial of the drug did not show any improvements in cognitive decline, but the other trial did show some modest effects in patients who got the highest doses.

In November 2020 an independent FDA committee declined to endorse the drug for approval. Yet, by June 2021, the drug was approved anyway.

Within the pharmaceutical industry, the approval of Aduhelm initially sparked optimism that the FDA might open its doors to more biomarker-based approvals. However, that optimism wasn’t shared by the wider scientific community.

Three members of the independent committee that had advised against the drug’s approval resigned in protest. Based on the inconsistent data, major hospital systems like Mt. Sinai and the Cleveland Clinic have indicated they won’t prescribe the drug.

Part of the controversy around Aduhelm’s approval has centered around allegations of an especially close working relationship between the FDA and Biogen leading up to the drug’s approval. As STAT first reported, Biogen launched an internal effort called Project Onyx to try to convince regulators to approve the drug, and some FDA officials eventually played active roles in the drug’s approval, including joint presentations before external experts.

In a July 9 letter, Janet Woodcock, acting FDA Commissioner, called for HHS-OIG to conduct an external review that would investigate this working 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,” she wrote on Twitter.

While the HHS-OIG investigation was spurred by the Aduhelm controversy, this review will not focus on reviewing the scientific evidence behind Aduhlem (or any other drug, for that matter). Rather it will peek under the hood of the entire accelerated approval pathway to assess how, and when, the FDA chooses to allow drugmakers to go down that road.

HHS-OIG will review interactions between the FDA and outside parties, policies and procedures, and interrogate the FDA’s compliance with those procedures. The review will cover the Aduhelm review process but will also interrogate how the pathway was used to approve other drugs as well.

In a statement on Twitter Woodcock also said that the FDA will “fully cooperate” with the HHS-OIG review.

“Should the HHS OIG identify any actionable items and provide the agency with any recommendations, the FDA would review those expeditiously to determine the best course of action,” she said.

Should actions be required, they could have significant ramifications for drugs in the future, as this pathway is already an attractive option for other companies pursuing Alzheimer’s drugs.

Eli Lilly, for instance, is also working on an Alzheimer’s drug called donanemab, has released exploratory findings from a Phase II trial showing that the drug lowered levels of amyloid and other biomarkers and was associated with patient improvements. However, the bulk of the results rest on the drug’s efficacy against biomarkers of Alzheimer’s, rather than individual patient outcomes.

In a Q2 earnings call this week, Eli Lilly’s senior vice president and chief scientific medical officer, Daniel M. Skovronsky, noted that the FDA’s approval of Aduhelm “reflects a shift in policy and sets a new path for Alzheimer’s drug approval in the U.S,” and Eli Lilly still intends to file for FDA approval for donanemab using the FDA accelerated approval pathway by the end of the year.

But, that’s the same pathway that will now be under investigation by HHS-OIG.

Still, we might not see results anytime soon, so it is unclear how this news will impact future Alzheimer’s drugmakers seeking to capitalize on a perceived “shift in policy.” The report is scheduled to be released in 2023.

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