Promising cancer drugs that are fast-tracked for approval might not always work as expected. A new analysis indicated that around 40% of anti-cancer treatments rushed via the US Food and Drug Administration’s (FDA) fast approval pathways between 2013 and 2017 failed to show therapeutic effects in follow-up trials more than five years later.
Cancer medicines account for more than 80% of all accelerated approvals
The US FDA’s accelerated approvals program, established in response to the HIV/AIDS crisis of the 1980s and early 1990s, has allowed for the early approval of medications that cure serious illnesses and address an unmet medical need since 1992.
The FDA frequently grants accelerated approval, particularly for cancer medicines. One-third of all oncology drug approvals go through the accelerated approval process, with cancer medicines accounting for more than 80% of all accelerated approvals.
However, fast approvals rely on surrogate signs of a drug’s performance that are supposed to predict clinical benefit rather than directly measuring it. Cholesterol levels, for example, are a proxy marker for heart disease, but in post-approval confirmatory trials, pharmaceutical companies must demonstrate that a newly licensed medicine decreases death from heart disease.
The desired clinical objective in cancer trials is to demonstrate that patients live longer with a specific treatment, also known as overall survival. However, trials frequently employ a proxy measure of progression-free survival, which is how long a person lives with cancer before it worsens.
Analyzing FDA accelerated approvals of cancer drugs over the past decade, clinician-researchers at Brigham and Women’s Hospital in Boston extended on previous research that examined the outcomes of the program, which has been criticized for using lower regulatory standards than traditional approvals for expensive drugs of uncertain benefit.
“Although accelerated approval can be useful, some cancer drugs do not end up demonstrating benefit in extending patients’ lives or improving their quality of life,” epidemiologist Ian Liu and colleagues write in their published paper.
41 percent or 19 of the 46 cancer medications granted fast approval during that period, did not extend patients’ lives or improve their quality of life
Between 2013 and 2023, 59 cancer medicines were provisionally approved through the FDA’s rapid approval procedure, covering 129 indications or uses.
By mid-2023, seven of the 46 therapeutic indications approved between 2013 and 2017 had yet to receive the findings of confirmatory trials. Meanwhile, ten drugs had been discontinued.
However, the researchers discovered that 41 percent, or 19 of the 46 cancer medications granted fast approval during that period, did not extend patients’ lives or improve their quality of life.
Add in the seven continuing trials for which results are still pending, and the percentage jumps to 57% of fast-tracked cancer medications failing to show benefit five years after approval.
There are some indications that the system is improving. Fast-tracked medications that proved useless in follow-up trials were removed from the approval process more quickly, in only 3.6 years in 2017, compared to approximately 10 years in 2013.
Drug companies are taking longer to demonstrate that treatments are successful in mandatory post-approval studies, which means that such drugs will be available for years before clinicians and patients may be certain that ‘ stand-in’ surrogate markers represent clinical benefit.
The researchers discovered that the time it took for fast-tracked treatments to be awarded traditional approval if they demonstrated benefit increased throughout the study, from 1.6 to 3.6 years.
This is consistent with recent research demonstrating that delays in confirmatory trials can result in some medications being administered for more than a decade without proving that they help patients live longer or better lives.
This is not the only concern affecting clinical cancer research. In 2022, researchers discovered that data from more than half of 300 audited clinical trials from the previous decade remained inaccessible, even though those trials supported anti-cancer drug approvals. This means that academics and physicians cannot examine the evidence on which the FDA made its decisions.
However, accelerated approvals remain controversial, particularly in light of the FDA’s 2021 decision to approve aducanumab, an antibody for Alzheimer’s disease that removed protein clumps linked with the disease but did not slow the cognitive decline. This year, Biogen, the manufacturer, will stop aducanumab, citing other priorities.
The US government announced legislative reforms to the accelerated approval pathway in June 2022, which academics said were “long overdue.” These revisions will allow the FDA to force drug companies to initiate confirmatory trials before issuing fast clearances, as well as report on their research progress twice a year.
The study was published in the Journal of the American Medical Association.