Promising cancer drugs that get accelerated approvals don’t always work as hoped. A new studio found that about the 40% of cancer therapies initiated through the accelerated approval pathway of the US Food and Drug Administration (FDA) between 2013 and 2017 have shown no clinical benefit in follow-up studies more than five years later.
What is the FDA Accelerated Approvals Program
Created in response to the HIV/AIDS epidemic of the 1980s and early 1990s, the US FDA’s Accelerated Approvals program has allowed the early approval of drugs that treat serious conditions and meet a medical need since 1992 dissatisfied. Accelerated approvals by the FDA are common, especially for cancer therapies. One-third of all oncology drug approvals go through the accelerated approval pathway, and more than 80% of all accelerated approvals are granted for cancer therapies.
However, accelerated approvals rely on surrogate markers of a drug’s efficacy that are believed to predict clinical benefit, without directly measuring benefit. Cholesterol levels, for example, are a surrogate indicator of heart disease, but what drug companies must demonstrate, in confirmatory post-approval studies, is that a newly approved drug prevents death from heart disease.
In cancer trials, demonstrating that patients live longer with a given treatment – referred to as overall survival – is the ideal clinical endpoint. But studies often use a surrogate measure of progression-free survival, which is how long a person lives with cancer before it gets worse.
I study
Analyzing accelerated FDA approvals of cancer drugs over the past decade, clinical researchers at Brigham and Women’s Hospital in Boston delved into research that had previously scrutinized the outcomes of the program, which has been criticized for using lower regulatory standards compared to traditional approvals, for expensive drugs with uncertain benefit.
“While accelerated approval can be helpful, some cancer drugs don’t end up demonstrating benefits in extending patients’ lives or improving their quality of life“, write epidemiologist Ian Liu and his colleagues in their study.
Between 2013 and 2023, 59 cancer drugs received provisional approval through the FDA’s accelerated approval pathway, spread across 129 indications or uses. But the 41% – or 19 of the 46 cancer drugs granted accelerated approval between 2013 and 2017 – it did not extend patients’ lives or improve their quality of life, the researchers found. If we add the seven ongoing studies for which the results are not yet available, the figure rises to 57% of fast-tracked cancer drugs showing no benefit five years after approval.
There are, however, some signs that the system is improving. Fast-track drugs that proved ineffective in follow-up studies were withdrawn from the approval process more quickly, in just 3.6 years in 2017 compared to about 10 years in 2013.
But drug companies are taking longer to prove that drugs are effective in mandatory post-approval studies, meaning that such drugs are available for years before doctors – and their patients – can be sure that the surrogate markers actually reflect the clinical benefit.
The researchers found that the time it took for fast-track drugs to gain mainstream approval if they showed benefit lengthened over the study period, increasing from 1.6 years to 3.6 years over the duration of the study. This parallels other research showing that delays in confirmatory trials can lead to some drugs being used for more than a decade without confirming that they help patients live longer or better lives.
The problems of clinical cancer research
This is not the only problem plaguing clinical cancer research. A 2022 study found that data from more than half of the 300 controlled clinical trials over the past decade remained inaccessible despite such studies underpinning the approval of cancer drugs. This means that researchers and doctors cannot verify the evidence on which the FDA based its decisions.
In June 2022, the US government approved legislative reforms to the expedited approval pathway, which researchers said were “long awaited”. These changes will mean that the FDA will be able to require that drug companies have at least started confirmatory studies before granting accelerated approvals and will have to report on the progress of their studies twice a year. Time will tell what impact these reforms will have.
The study was published in the Journal of the American Medical Association.
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