The FDA's accelerated approval pathway, intended to provide quicker access to medications for serious conditions, is under increased scrutiny following several high-profile drug withdrawals and concerns about the use of surrogate endpoints. Pfizer's Oxbryta, a sickle cell disease therapy, was recently pulled from the market due to safety concerns, highlighting the risks associated with this expedited approval process.
Accelerated Approval: A Double-Edged Sword
Initiated during the AIDS pandemic, the accelerated approval program has facilitated the entry of nearly 300 new drugs into the market, offering patients access to these treatments an average of 3.2 years earlier than traditional approvals. While many accelerated approvals have come in infectious disease and oncology, the pathway has recently been leveraged by several high-profile neurological and rare disease therapeutics. However, the program relies on surrogate endpoints, such as biomarkers, that are "reasonably likely to predict clinical benefit," necessitating confirmatory trials to verify actual clinical benefit.
Concerns Over Biomarkers and Confirmatory Trials
Experts are raising concerns about the validity of using biomarkers to predict clinical benefit and risk. Joel Perlmutter, a professor of neurology at Washington University School of Medicine in St. Louis, stated, "Using a biomarker to predict clinical benefit for both the benefit and the risk is nearly impossible." He added that current biomarkers often indicate target engagement but rarely provide insights into safety, which requires clinical observation.
Delays in confirmatory trials further compound the issue. A 2022 NPR report revealed that 42% of outstanding confirmatory studies either took over a year to commence after accelerated approval or had not yet begun. Perlmutter noted that these follow-up studies are rarely conducted promptly, potentially leaving drugs with harmful effects and inadequate benefits on the market for extended periods. For example, Oxbryta remained available for nearly five years before being withdrawn.
Joseph Ross, a professor of medicine and public health at Yale School of Medicine, emphasized the need for validated surrogate markers with clinical evidence linking them to clinical outcomes. He stated, "It seems like a fool’s errand to continue to allow products to be approved on the basis of the same fallible surrogate markers over and over. I think we need a much better sense of the surrogate markers that are being used as efficacy endpoints."
Differing Perspectives on Biomarker Reliability
While some experts express skepticism about biomarkers, particularly in complex diseases like Alzheimer's and ALS, others argue for their reliability in rare, genetic diseases. Emil Kakkis, CEO of Ultragenyx, contends that in rare genetic diseases, biomarkers often represent the underlying cause of the disease and consistently translate into clinical benefit. He stated, "In all cases, that’s transformed into clinical benefit down the road. It has not failed."
Proposed Solutions and Future Directions
To address the shortcomings of the accelerated approval pathway, experts suggest several improvements. These include establishing firmer and shorter deadlines for confirmatory trials to ensure timely evidence of drug safety and effectiveness. Additionally, concerns have been raised about potential biases in the FDA's funding structure, where a significant portion of the budget comes from companies seeking approval. Perlmutter noted that this could influence judgment, especially in accelerated approval decisions.
Despite the challenges, the accelerated approval pathway remains a valuable tool for expediting access to potentially life-saving medications. As Kakkis stated, "The biomarker-based approval of HIV drugs was not a compromise. It’s far superior to doing it any other way."
