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OIG Recommends Changes in FDA Accelerated Approval After Flagging Concerns With Aduhelm, Other Drugs

NEW YORK – The US Department of Health and Human Services' Office of Inspector General posted a report Tuesday outlining recommendations to improve consistency and transparency in the US Food and Drug Administration's accelerated approval pathway.

The report focuses on drugs the FDA has greenlit through the accelerated approval pathway that have raised concerns, including Biogen's beta-amyloid-targeting Alzheimer's disease drug Aduhelm (aducanumab). Biogen, the manufacturer of Aduhelm, has since discontinued selling the drug amid controversy about its efficacy. 

In its report, the OIG made two recommendations for the FDA to refine the accelerated approval pathway. First, the OIG recommended that the FDA define specific factors that would trigger an application's review by the agency's accelerated approval council. Second, the OIG advised that the FDA should take steps to ensure that appropriate documentation of meetings with sponsors are included in drug approval administrative files.

The OIG acknowledged in its report that the FDA concurred with the latter recommendation, but did not concur with the first, arguing that such a requirement would be inefficient. The FDA instead suggested having leadership from its drug and device centers advise on such applications.

To develop its recommendations, the OIG reviewed a sample of 24 drugs approved through the accelerated approval pathway to determine whether the agency's review of these products deviated from its typical practices and whether issues brought to light in the controversial approval of Aduhelm were present for other approvals. The OIG examined 10 drugs with approvals identified as concerning during interviews with stakeholders, as well as a random sample of 14 other drugs from the roughly 270 drugs that had been approved through the accelerated approval pathway through 2021.

In addition to Aduhelm, the OIG found concerning the FDA's accelerated approval of two other drugs, Sarepta Therapeutics' Exondys 51 (eteplirsen), an antisense oligonucleotide approved in 2016 to treat Duchenne muscular dystrophy patients with certain genetic mutations, and Covis Pharma's Makena (hydroxyprogesterone caproate), approved in 2011 to reduce risk of preterm birth. 

Neither Aduhelm nor Makena, for which the FDA withdrew approval in 2023, are currently on the market. Sarepta's clinical trial to confirm the benefit of Exondys 51 was initially scheduled to be completed in 2021 but has been delayed.

In the case of these three drugs, the FDA approved them despite concerns from its reviewers and advisory committees. Additionally, in reviewing Aduhelm and Exondys 51, the FDA considered analyses that were not included in the drug sponsors' original analysis plans, according to the OIG. 

For Aduhelm, not just FDA staffers and its advisory committee but also experts in the broader medical and research communities had raised concerns about the mixed efficacy data on the drug. A congressional investigation into the approval found the review process was "rife with irregularities" and questioned the extent of the interactions between the FDA and Biogen. There were also instances of meetings with Biogen that were not fully documented in administrative files. 

Under the accelerated approval pathway, the FDA can approve drugs more quickly by basing regulatory decisions on how treatments affect biomarkers likely to predict clinical benefits. Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, in recent years has emphasized his interest in providing flexibility to developers of rare disease therapies through this pathway, particularly for gene therapies.

"In using the accelerated approval pathway, FDA must balance the goal of expediting the development and review of new drugs when there are no alternative treatments with the risk of approving drugs without confirmed clinical benefit," the OIG wrote. "Although FDA has latitude in making decisions, these three cases underscore the need for additional guardrails in certain circumstances."

Since drugs approved through the accelerated approval pathway do not have to demonstrate clinical improvements before approval, there's a risk that such drugs will not provide benefits for patients, the OIG said, adding that this is why it's critical for the FDA to establish safeguards and transparency into its decision-making.