OIG Report Seeks Better Oversight, Records for FDA’s Accelerated Approvals

In the waning days of the Biden administration, a report from HHS' Office of the Inspector General (OIG) called for greater accountability of the FDA’s accelerated approval pathway, including better documentation of meetings between FDA staff and drug sponsors and “guardrails” that would flag when an accelerated approval council should weigh in on applications.¹

HHS OIG logo | Image credit: HHS

The report, triggered by the controversial 2021 approval of aducanumab (Aduhelm) for Alzheimer disease, shed light on the increased use of the FDA's expedited process for therapies that address unmet medical needs. Created in 1992, the Accelerated Approval Program offers a way to get novel therapies to patients quickly, perhaps years ahead of schedule compared with waiting on results from a phase 3 trial.² For patients with cancer or children with an incurable inherited disease, the pathway can literally mean the difference between life and death.

Approval through this route often involves the use of a surrogate end point, which means accelerated approval is based on a measure other than overall survival. Accelerated approval is also conditional; it can be retained only with results from a confirmatory trial involving a larger number of patients. If those results do not show the effectiveness of the early findings, the approval can be withdrawn or the sponsor can voluntarily pull the drug from the market. Both have happened in the past 5 years; recent actions often involve subsequent indications for an approved drug being withdrawn. The HHS OIG report notes that both the aducanumab episode and 2022 legislative changes brought more oversight into this process, including a requirement that the confirmatory trial start before FDA grants accelerated approval.

The accelerated pathway is widely used in oncology, with 59 cancer drugs getting to market this way from 2013 to 2023.³ A report in the August 2024 issue of Evidence-Based Oncology™, published by The American Journal of Managed Care^® (AJMC^®), found that 9 cancer drugs had received accelerated approval in 2024 through June, compared with 5 for all of 2023.²

The HHS OIG report, issued January 14, 2025, has been overshadowed by the uproar over President Donald J. Trump’s firing of 18 inspectors general (IGs) across the federal government. The dismissals came without the required 30-day notice to Congress and included HHS IG Chrisi Grimm, who joined the office in 1999 and had led it since 2022. Most of the work of the OIG involves oversight of Medicare and Medicaid; its December 2024 report to Congress estimated audits would result in a recovery of $7.13 billion.

Issues involving the costs of accelerated approvals are front and center among clinicians in practice. During a session of AJMC’s Institute for Value-Based Medicine hosted by Mayo Clinic in 2024,⁴ panelists cited data that show 22% of the cancer drugs approved by the accelerated pathway between 2013 and 2017 were later taken off the market.

Chelsee Jensen, PharmD, BCPS | Image credit: LinkedIn

“I really feel like the accelerated approval phase should be [like] we are dating you as a drug,” Chelsee Jensen, PharmD, BCPS, senior pharmacy specialist and pharmaceutical formulary manager, told the audience. She called for these medications to be priced differently, based on their quality-adjusted life-years, until a confirmatory trial is completed. Only then should manufacturers be allowed to charge full price.

“Think about the cost that has been spent by Medicare on a drug that is essentially not effective [or is] no more effective than what the standard of care is,” she said. “What a waste of money. What a waste of patient hope, and a huge price tag at that…. [It’s also a] huge disruption when you have to go back and take those patients off that drug.”

What Led to the Report

The HHS OIG report on the FDA's accelerated approval pathway may be a departure from the office’s usual work, but it’s a topic that matters to Congress’ fiscal hawks, who want to bring down Medicare spending. The report notes 2 problems with the accelerated pathway:¹

• A third of sponsors were found to drag their feet on confirmatory trials, and
• Payers, especially Medicare, pay full price for drugs that may later turn out to be less than fully effective. Authors noted, “Medicare and Medicaid spent more than $18 billion from 2018 to 2021 for accelerated approval drugs with incomplete confirmatory trials past their original planned completion dates.”

Aducanumab’s controversial approval came despite a vote from an FDA advisory panel recommendation against approval. The agency’s decision to approve it anyway triggered resignations from 2 panel members, one of whom told The Washington Post he did not “wish to be part of a sham process.”

However, following reports by STAT and the investigation by Congress uncovered accounts of off-the-books meetings between regulators and Biogen, Medicare only offered limited coverage for the drug. With alternatives available, Biogen pulled aducanumab from the market in January 2024.

The Review Process

The HHS OIG report reviewed a sample of 24 drugs from the 278 approved via the accelerated pathway through the FDA’s Center for Drug Evaluation and Research (CDER) through 2021; 19 were drugs and 5 were biologics. Investigators purposely selected 10 that had raised concerns with stakeholders during interviews; the other 14 were selected at random.¹

For each drug, the review sought to determine: (1) whether the FDA followed the original analysis plans with regard to end points; (2) what happened when scientific disputes or informal disagreements arose, including cases that involved a negative vote from an advisory committee; and (3) whether meetings between the FDA and sponsors were properly documented.

Of the 24 drugs, reviewers found 3 approved drugs raised concerns. In 2 cases, reviewers note that FDA leadership flagged the possibility that sponsors could lose funding and stop research in areas without viable treatments.

Aducanumab

This drug raised flags in all 3 areas. The review found that FDA “veered from a best practice” by examining data not in the original analysis plan when it reviewed data from the application for traditional approval “to instead seek accelerated approval.”

The HHS OIG report states, “When it appeared that the drug could not achieve traditional FDA approval by demonstrating clinical benefit, FDA considered whether the drug had an effect on a surrogate endpoint that supported accelerated approval.” The report traces the complex rationale used to shift to accelerated approval for the surrogate end point, a reduction in amyloid plaques, when the sponsor had a pair of identically designed trials that produced different results. In addition to the significant concerns raised by the advisory committee as well as the CDER Office of Biostatistics, the report notes that files show evidence of “meetings being mentioned but not further documented or summarized,” a problem not limited to aducanumab.

“Although these meetings were documented as having happened, the lack of details regarding the meetings makes it difficult to determine whether the meetings contributed significantly to FDA’s decision-making," the report found.¹

Eteplirsen

This drug, marketed as Exondys 51 to treat Duchenne muscular dystrophy, received accelerated approval in 2016. Here, reviewers found FDA deviated from the original plan. Although the sponsor sought accelerated approval based on a clinical end point of improved mobility, the FDA sought a surrogate end point of dystrophin production, which had been a secondary measure. Later, FDA asked for additional data because the initial data were not “reliable or interpretable,” the report stated; regulators then used data from a different trial “that was still in progress.”¹

After the FDA review team did not want to approve the drug following all these changes, the CDER director overruled; the report notes that the sponsor “would lack funding to continue researching [eteplirsen] or similar drugs, which could have a negative impact on the patient population with Duchenne muscular dystrophy.”

Hydroxyprogesterone caproate (HPC)

This drug, sold as Delalutin, reduces the risk of preterm birth. The report notes that although all reviewers ultimately supported accelerated approval, this came after many rounds and “sponsor commitments to resolve concerns through confirmatory trials after approval.” Reviewers raised issues with HPC’s surrogate end point.

Recommendations

HHS OIG recommended that FDA “strengthen guardrails in certain circumstances to ensure appropriate and consistent use of the accelerated approval pathway.”

It called for 2 specific steps:

• FDA should “define specific factors that would require FDA’s accelerated approval council to advise on certain drug applications.” The agency did not agree with this recommendation.
• FDA agreed that it should “take steps to ensure that appropriate documentation of meetings with sponsors is included in drug approval administrative files.”¹

Laura Joszt, MA, contributed to this report.

References

1. Office of the HHS Inspector General. How FDA used its accelerated approval pathway raised concerns in 3 of 24 drugs reviewed OEI-01-21-00400. HHS. Published January 2025. Accessed January 14, 2025. https://oig.hhs.gov/documents/evaluation/10160/OEI-01-21-00400.pdf
2. Wonsettler T. Cancer drugs speed to accelerated approvals, then hit the brakes in timely, clinically beneficial confirmatory trials. Am J Manag Care. 2024;30(SP9):SP722-SP724. doi:10.37765/ajmc.2024.89597.
3. Matthius A. Accelerated approval of cancer drugs: how many verify clinical benefit? AACR blog. April 8, 2024. Accessed January 25, 2025. https://www.aacr.org/blog/2024/04/08/accelerated-approval-of-cancer-drugs-how-many-verify-clinical-benefit/
4. Joszt L. Navigating the complexities of cancer care: cannabis and cost considerations. Am J Manag Care. 2024;30(SP11):SP828-SP829