FDA’s Accelerated Approval Pathway Under Scrutiny for Key Drug Approvals

The Office of Inspector General (OIG) issued a report raising concerns over the FDA’s accelerated approval process, focusing on 3 drugs that indicate flaws in judgment, transparency, and adherence to procedural safeguards. The 32-page report examines the aducanumab (Aduhelm; Biogen), eteplirsen (Exondys; Sarepta), and hydroxyprogesterone caproate (Makena; Covis Pharma Group), highlighting issues that raise questions about the effectiveness and consistency of the pathway.¹

FDA US Food and Drug website in browser with company logo | Image Credit: © Postmodern Studio - stock.adobe.com

The report examines the approval processes for 24 drugs, of which 3 raised significant concerns. It outlines deviations from standard practices, including reliance on unplanned analyses, approval despite internal objections, and inadequate documentation of meetings. These lapses led to calls for improved oversight and greater transparency in the accelerated approval pathway, particularly as aducanumab and hydroxyprogesterone caproate have been withdrawn from the market.¹

The FDA’s Accelerated Approval Process

The FDA’s accelerated approval pathway is designed to expedite the development and review of therapies for serious and life-threatening conditions, allowing drugs to be approved based on surrogate end points. However, this approach comes with risks, as surrogate end points do not guarantee efficacy. Controversies surrounding high-profile drug approvals and subsequent market withdrawals have placed this pathway under increased scrutiny.¹

The FDA has multiple pathways for drug approval, including traditional and accelerated approval pathways. Both require data supporting the safety and efficacy of the drug through clinical trials, progressing from smaller to larger populations to assess dosage, adverse effects (AEs), and treatment response. In traditional approval pathways, trials must show a clinical benefit impacting patient outcomes, such as improved survival or quality of life.¹

In contrast, the accelerated approval pathway allows the use of surrogate end points, which are indirect measures, such as tumor shrinkage, that are likely to predict clinical benefit, but not to the extent of meeting the end points. Although surrogate end points can expedite access to potentially life-saving treatments, they carry inherent risks. Drugs approved through the accelerated pathway are still required to meet safety and effectiveness standards, but their clinical benefit may remain unestablished until post-approval confirmatory trials are completed. The FDA’s Center for Drug Evaluation and Research approved 307 drugs through this pathway from 1992 to 2023, highlighting its role in modern drug development.¹

Controversy Over Aducanumab Approval

Aducanumab’s approval in 2021 for Alzheimer disease was one of the most controversial decisions in the FDA’s history, and the report highlighted several irregularities. These included undocumented or incomplete meetings between the FDA and the company, and the reliance on data not included in the company’s original submission, which raised significant transparency concerns.^1,2

Aducanumab approval announcement on computer screen | Image Credit: © Tada Images - stock.adobe.com

“The approval process for aducanumab specifically was very strange,” said Pamela Spicer, a neuroscience expert and therapy area director at Citeline, in an interview with Pharmacy Times^®. “The FDA worked unusually closely with Biogen during the review process, and the agency went against the advisory committee recommendation in its approval.”²

The approval decision was based on contradictory data from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) trials, which showed that only the high-dose treatment arm in EMERGE demonstrated cognitive improvement and ENGAGE showed no significant benefit. Despite having identical study designs and the same primary end point, differing study protocols and the premature termination of both trials contributed to these results. Through subgroup analyses, the company identified 2 possible explanations.²

The first is that the ENGAGE trial had a greater number of participants who experienced rapid cognitive decline compared to the EMERGE trial. Removing these outliers from the dataset resulted in more similar outcomes between the trials. The company’s second explanation cited that fewer participants in the ENGAGE trial had been administered the higher doses of the drug, which may have influenced the findings.²

Additionally, there was controversy over the original labeling, which lacked guidance on disease stage or confirmed amyloid pathology. In April of 2022, Medicare decided to restrict coverage of aducanumab to clinical trial participants. Health care professionals also announced that they would not be administering the drug due to concerns about its safety and AEs. Aducanumab was removed from the market in November 2024, further prompting and supporting investigations into the FDA’s accelerated approval pathway.²

Eteplirsen and Hydroxyprogesterone Caproate

The OIG report also investigated the accelerated approvals of eteplirsen for Duchenne muscular dystrophy and hydroxyprogesterone caproate to prevent preterm births.¹

The eteplirsen approval in 2016 relied on unplanned analyses during FDA review, raising procedural red flags. The FDA review team concluded that the drug should not be approved because the surrogate end point was deemed too small to predict a clinical benefit. However, the CDER director argued that without FDA approval, funding for continued research would be at risk, potentially harming the patient population with Duchenne muscular dystrophy. Despite the breakout of a formal dispute, the FDA Commissioner upheld the approval. As of 2025, eteplirsen's confirmatory trial is incomplete.¹

Hydroxyprogesterone caproate, which was pulled from the market in 2023, faced a similar trajectory. Regardless of concerns over the surrogate end point and clinical trial design, the sponsor agreed to submit additional data after a formal dispute. Eventually, the FDA approved eteplirsen even though it failed to demonstrate clinical efficacy.¹

Clinical trial data on a computer screen | Image Credit: © pakbung - stock.adobe.com

Both cases highlight significant gaps in the oversight and enforcement of post-approval requirements, raising questions about the use of surrogate end points and the effectiveness of accelerated approval processes.

Report Findings and Recommendations

The OIG’s report highlighted 3 key issues in the FDA’s accelerated approval pathway: reliance on unplanned analyses, approvals despite internal objections, and insufficient documentation of sponsor meetings. The OIG recommended clearer guidelines for input from the FDA’s Accelerated Approval Council and better documentation of sponsor interactions, though the FDA only agreed to improve documentation.¹

“Given these outliers and the importance of FDA’s role in approving drugs for the public, it is critical that FDA have appropriate guardrails in place to offset risk and ensure consistent and appropriate practices,” stated the authors in the official report. “FDA’s primary guardrail, the confirmatory trial, has been limited in execution. As we have also shown in previous work, many of these trials extend past their originally planned completion dates, and FDA faces challenges in withdrawing approval from a drug that fails to confirm clinical benefits.”¹

New authorities granted to the FDA in late 2022 include the ability to require confirmatory trials to begin before or shortly after approval, and the establishment of a new intra-agency council. These measures aim to improve oversight, address risks, and restore confidence in the system to ensure timely, safe, and effective treatments for patients.¹

With the uncertain future of health policy in the United States, the FDA faces mounting pressure to refine its processes amidst a shifting landscape of government and agency leadership. Stricter safeguards and adherence to established protocols will be essential to restore confidence in the system, and it remains to be seen how these changes will impact the FDA’s ability to deliver timely, safe, and effective treatments.

REFERENCES

1. Office of Inspector General. How FDA used its accelerated approval pathway raised concerns in 3 of 24 drugs reviewed. U.S. Department of Health and Human Services. January 2025. Accessed January 17, 2025. https://oig.hhs.gov/documents/evaluation/10160/OEI-01-21-00400.pdf

2. New treatments are changing the future of Alzheimer disease. Pharmacy Times. August 30, 2024. Accessed January 17, 2025. https://www.pharmacytimes.com/view/new-treatments-are-changing-the-future-of-alzheimer-disease