Transforming the FDA’s Fast-Track Approval Process Faces Multiple Withdrawal Challenges

In the previous month, Pfizer’s Oxbryta, a treatment for sickle cell disease, was removed from the market. This decision came after the therapy, which had received accelerated approval in 2019, was found to carry risks of death and other serious issues, underlining the hazards of rapidly approving drugs via this process.

The FDA’s accelerated approval initiative has facilitated the introduction of nearly 300 new therapies, allowing patients to access these medications approximately 3.2 years sooner than through the standard approval route. A recent report from PhRMA indicated that millions of patients benefited from quicker access to clinical advantages, including extended life and reduced symptom severity.

Initially developed in response to the AIDS crisis, the accelerated approval pathway has primarily been utilized in infectious diseases and cancer treatments. Recently, however, this avenue has seen a rise in approvals for notable neurological and rare disease therapies. In the last five years, the FDA has approved innovative treatments for Alzheimer’s, ALS, and Duchenne muscular dystrophy, among others.

Although around 50% of drugs sanctioned through this pathway, including Biogen and Eisai’s Leqembi for Alzheimer’s and AbbVie’s Elahere for ovarian cancer, attained full traditional approval, instances like Oxbryta demonstrate that some therapies ultimately fail to receive such validation. Others, like Biogen’s Aduhelm and Takeda’s Exkivity, faced similar fates of withdrawal following inadequate confirmatory study outcomes.

Joel Perlmutter, a neurology expert at Washington University, noted, “The accelerated pathway allows for swift advancement of drugs crucial for patients with severe conditions,” but cautioned about its execution. This approval type relies on surrogate endpoints—biomarkers that may suggest potential clinical benefit—prior to confirming trials being completed post-approval.

Gene therapies for rare conditions seem to be perfect candidates for accelerated approval, as biomarkers are central to these studies. According to Emil Kakkis, CEO of Ultragenyx, this pathway has only been utilized for a couple of rare disease therapies, like Sarepta Therapeutics’ Elevidys for DMD and bluebird bio’s Skysona for adrenoleukodystrophy, indicating a need for broader adoption.

Kakkis pointed out that enhancing access to the accelerated approval process could significantly reduce development expenses in the rare disease domain, potentially leading to the development of three times as many therapies. He advocated for a shift in focus toward primary disease activity biomarkers, emphasizing disease causation over merely treating symptoms.

Accelerated Approval Expands Its Reach

The accelerated approval system was launched in 1992, closely aligned with the HIV/AIDS pandemic. Initially, a significant majority of drugs approved via this route were for infectious diseases. Over the last two decades, a vast array of cancer therapies has emerged from this pathway, but we are now witnessing a third phase with approvals for neurological and rare diseases.

Controversial approvals, such as Biogen and Eisai’s Aduhelm, sparked intense debate regarding their clinical effectiveness. Subsequent market withdrawals and trial failures, including Oxbryta’s withdrawal, have prompted scrutiny of the accelerated approval program’s true value.

Joseph Ross, a Yale professor, remarked on the necessity for lessons learned from oncology’s experience to be heeded more broadly across FDA divisions, emphasizing the importance of timely confirmatory trials and focusing on measurable clinical outcomes.

Improving Biomarker Utilization

Perlmutter elaborated on the challenges of basing accelerated approval on biomarkers, stating that while they may indicate target engagement, they often do not suffice to ascertain safety. This dilemma is compounded by the frequent delays in confirmatory trials. In 2022, a report revealed that 42% of outstanding confirmatory trials faced significant delays.

Ross criticized the FDA for not necessitating strong validation of surrogate markers through clinical algorithms correlating with actual outcomes, reinforcing that reliance on these markers often leads to overlooked safety concerns.

Kakkis reinforced that while biomarkers are often problematic for complex conditions like Alzheimer’s, they present reliable endpoints for rare genetic diseases, where a clear relationship between the biomarker and disease causation is typically established.

The Relevance of Accelerated Approval

Kakkis argued against viewing expedited approval as less reliable, asserting that utilizing biomarkers for HIV treatments was vital and effective. The FDA is making efforts to enhance oversight of the approval process following acknowledged delays in confirmatory trials, bolstered by recent legislative changes to improve accountability.

Experts concur that further reforms are necessary, particularly regarding stricter timelines for confirmatory trials to furnish essential data swiftly for clinicians and patients. Concerns over potential biases arising from the FDA’s funding model have also been raised, highlighting the need for vigilant scrutiny to maintain the integrity of the approval process.