A recent cohort study published in JAMA Oncology has revealed that the use of cancer medications significantly declines after the withdrawal of their accelerated approval by the U.S. Food and Drug Administration (FDA), even when these drugs remain available for other indications.
Researchers led by Catherine S. Hwang, MD, MSPH, from the Division of General Internal Medicine and Geriatrics at Oregon Health and Science University, investigated changes in cancer drug utilization following the publication of negative confirmatory trials for medications initially granted accelerated approval.
Accelerated Approval Pathway and Post-Market Monitoring
The FDA's accelerated approval program allows medications targeting serious diseases to reach the market based on preliminary efficacy evidence, with the requirement that pharmaceutical companies conduct post-approval trials to confirm clinical benefits. If these confirmatory trials fail to demonstrate efficacy, the indication should be removed from the product's label.
However, these medications often remain available if they have other approved indications and may continue to be prescribed off-label for the withdrawn indication, raising concerns about continued patient exposure to potentially ineffective treatments.
Study Findings on Drug Utilization Patterns
The research team identified three cancer medications that had their accelerated approval withdrawn for four indications between January 2020 and December 2022:
- Atezolizumab for breast cancer and urothelial cancer
- Idelalisib for follicular lymphoma
- Romidepsin for peripheral T-cell lymphoma
The comprehensive study included 762,752 patients across four cohorts corresponding to these cancer types. Researchers measured changes in both incident and prevalent medication use following the first public reporting of negative trial results.
"We observed that use of these medications increased following accelerated approval and before any negative results were reported from post-approval studies," the researchers noted. "However, once the confirmatory studies published negative findings, use of these medications decreased significantly despite their ongoing availability."
Significant Decline in Atezolizumab Use
The study highlighted atezolizumab as a notable example. Its use increased by 16 patients per 1 million patients (95% confidence interval [CI] = 12 to 21 patients/million) with breast cancer before negative confirmatory findings were published. Following publication of negative findings, atezolizumab use decreased by 28 patients per million (95% CI = −35 to −20).
Timing Disparities in Regulatory Actions
The researchers identified concerning variations in the timeline between regulatory actions:
- The time between accelerated approval and publication of negative confirmatory trial results ranged from 12 to 113 months
- The period between publication of negative trial results and withdrawal of FDA approval varied even more dramatically, ranging from 1 to 47 months
These timing disparities raise questions about how long patients may be exposed to medications that ultimately fail to demonstrate clinical benefit.
Implications for Regulatory Oversight
The findings underscore the importance of timely completion of post-approval studies and prompt regulatory action following negative results. The authors concluded that "ensuring timely completion of post-approval studies and enforcing appropriate regulatory actions based on negative trial results is necessary to minimize patient exposure to ineffective and potentially unsafe medications."
This study provides valuable insights into how clinical practice responds to evolving evidence and regulatory decisions, highlighting both the effectiveness of scientific communication in changing prescribing patterns and the need for more streamlined regulatory processes.
Balancing Access and Evidence
The accelerated approval pathway remains an important mechanism for providing earlier access to promising treatments for serious conditions. However, this research emphasizes the need for robust post-market monitoring and timely regulatory action to maintain the integrity of the approval process and protect patient safety.
Healthcare providers appear responsive to new evidence, as demonstrated by the decline in prescribing following negative trial publications. This suggests that effective communication of trial results can help guide appropriate clinical decision-making even before formal regulatory action occurs.
As the FDA continues to refine its accelerated approval process, this study provides important real-world evidence on how the current system functions and where improvements might be needed to better balance early access with scientific rigor.
