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The concept behind the accelerated approval pathway for cancer drugs by the US Food and Drug Administration (FDA) is straightforward: to get promising new cancer treatments to market and to patients faster. By allowing the use of surrogate markers—indicators such as tumor shrinkage or halted tumor growth—this pathway aims to expedite the availability of potentially life-saving therapies. In exchange, drug manufacturers agree to conduct confirmatory trials to validate the drugs’ effectiveness in improving overall survival and quality of life.
However, the speed of accelerated approvals often comes at a cost.
Surrogate Markers: A Double-Edged Sword
While surrogate markers facilitate quicker drug approvals, they don’t always predict the ultimate benefits of a treatment. Dr. Bishal Gyawali, an associate professor at Queen’s University, Kingston, Ontario, and a Medscape Medical News contributor, highlights that confirmatory trials, which can take years, frequently fail to show clinical benefits. A study revealed that 26 of 46 cancer drug indications granted accelerated approval between 2013 and 2017 failed to demonstrate a clinical benefit after at least five years of follow-up. Moreover, 10 of these indications were withdrawn during that period.
In a similar analysis by Gyawali and colleagues, only 20% of the 93 cancer drug indications that received accelerated approval from December 1992 through May 2017 demonstrated improvements in overall survival during follow-up confirmatory analyses. Despite these shortcomings, the accelerated approval pathway remains a prevalent method for getting drugs to patients sooner.
The Metastatic Patient Perspective
Dr. Julie R. Gralow, chief medical officer of the American Society of Clinical Oncology, argues that this pathway is particularly beneficial for metastatic patients, for whom curative options are often unavailable. In these cases, having access to new drugs, even with some uncertainty, is preferable. Dr. Ian T.T. Liu of Brigham and Women’s Hospital and Harvard Medical School concurs, noting that the accelerated pathway is sensible for metastatic settings due to limited alternatives. However, he cautions that the evidence required for FDA approval under this pathway is “easier to produce.”
The Issue of Surrogate Endpoints
Surrogate endpoints, such as progression-free survival, are commonly used in cancer drug trials. While progression-free survival is one of the more reasonable surrogates for overall survival, research suggests that the correlation between these endpoints can be weak. Dr. Liu emphasizes that progression-free survival “leaves a substantial amount of uncertainty as to a drug’s ultimate benefit.” Additionally, the use of overall response rates—measuring only tumor growth, shrinkage, or markers in the blood—for full approvals is concerning. This metric doesn’t account for drug toxicity, which can significantly impact a patient’s quality of life.
The FDA’s Balancing Act
Nathan I. Cherny, director of the Cancer Pain and Palliative Care Service at Shaare Zedek Medical Center in Jerusalem, notes that the FDA’s approach prioritizes availability over certainty. By lowering the threshold for approval, the FDA aims to provide drugs that have a chance of being beneficial. However, clinical trial designs can sometimes favor the investigational drug, making it appear more effective than it might be in real-world settings.
The Problem with Confirmatory Trials
One persistent issue is the timely completion of confirmatory trials. Dr. Liu points out that companies often delay these trials, leaving drugs on the market for years without definitive proof of their efficacy. However, the FDA gained new powers in 2022 to require that confirmatory trials be enrolling patients at the time of accelerated approval. The agency has also proposed using the same trial to provide evidence for both accelerated and full approvals, which could streamline the process and ensure more robust data collection.
Moving Forward
The goal should not be to eliminate the accelerated approval process, as it has successfully delivered powerful agents to patients quickly. Instead, the focus should be on maintaining the speed of approvals while ensuring robust and timely confirmatory trials to verify clinical benefits. Dr. Edward Cliff, a hematology trainee at Brigham and Women’s Hospital and a fellow at the Peter MacCallum Cancer Centre, underscores the importance of communicating any residual uncertainties about clinical benefits to patients when offering novel therapies. Providing patients with comprehensive information is crucial.
In summary, while the accelerated approval pathway for cancer drugs offers significant advantages, it also presents challenges. Ensuring that confirmatory trials are conducted promptly and that surrogate markers accurately predict clinical benefits is essential for the pathway to truly serve patients’ needs.
