Study Highlights Inconsistencies in FDA Accelerated Approval Pathway for Cancer Drugs
核心洞察
A recent study reveals that less than half of cancer (搜索) therapies granted accelerated approval by the FDA between 2013 and 2017 demonstrated clinical benefit in confirmatory trials within five years.
Nearly two-thirds of these drugs were converted to full approval, despite only 43% showing improved overall survival or quality of life, raising concerns about surrogate endpoint usage.
Experts emphasize the need for high-quality clinical outcomes to support conversion decisions and faster withdrawal of ineffective drugs to ensure the accelerated approval pathway's integrity.
A new study presented at the American Association of Cancer (搜索) Research (AACR) and published in the Journal of the American Medical Association (JAMA) has revealed potential weaknesses in the FDA's accelerated approval pathway for cancer drugs. The research, which analyzed 46 cancer drugs granted accelerated approval between 2013 and 2017, found that less than half demonstrated a clinical benefit in confirmatory trials within five years.
Key Findings on Accelerated Approvals
The study indicated that while 63% of the drugs received full approval, only 43% showed a clinical benefit, defined as improved overall survival (OS) or enhanced quality of life, in subsequent confirmatory trials. Alarmingly, 15% had no results available within the specified five-year period. This raises concerns about the evidence supporting the conversion of accelerated approvals to regular approvals.
Ian Liu of Brigham and Women’s Hospital and Harvard Medical School, a researcher involved in the analysis, noted, "Accelerated approvals make up a large percentage of new cancer (搜索) drug approvals, but we knew that oncology accelerated approvals are often not subsequently confirmed as having an effect on ‘hard’ clinical endpoints."
Further analysis of accelerated approvals between 2013 and 2023 showed that 37% were converted, with 40% based on OS and 44% on progression-free survival (PFS). A significant 60% of conversions relied on surrogate measures, such as response rates based on tumor shrinkage. The authors argue that these surrogate endpoints, like tumor shrinkage, "cannot by itself determine whether a drug offers patients a clinical benefit."
Concerns Over Surrogate Endpoints and Trial Design
The researchers expressed concern over the increasing reliance on surrogate endpoints for conversion and the use of confirmatory trials that extend a drug's use into new areas, such as earlier lines of therapy. This approach may not address the uncertainty surrounding the originally approved indication.
Edward Cliff, lead author and a haematology fellow at the Programme on Regulation, Therapeutics, and Law (PORTAL), emphasized that "The FDA relinquishes significant leverage once it converts accelerated approvals to regular approval – it is harder to ensure timely completion of further trials, and harder to withdraw drugs – so the evidence used to justify these decisions is important."
FDA's Response and Future Directions
In response to these concerns, the FDA has initiated efforts to tighten the accelerated approval system. These measures include withdrawing accelerated approvals for cancer (搜索) drugs that fail to demonstrate benefit in subsequent studies and requiring that confirmatory trials be well underway before granting clearance. An example of this stricter approach is the recent rejection of Regeneron’s lymphoma (搜索) therapy, odronextamab.
Liu acknowledged the potential benefits of the accelerated approval pathway when drugs are subsequently proven effective. However, he also stressed the importance of "faster appropriate withdrawal decisions" to remove ineffective drugs from the market, ultimately serving patients' best interests.
"While our study showed an increase in the time between accelerated approval and conversion to regular approval, we believe that conversion decisions should be both timely but – more importantly – supported by high-quality clinical outcomes, and that this is critical to the proper functioning of the accelerated approval pathway," Liu concluded.