Promising cancer drugs that are fast-tracked through approvals don’t always work as hoped. A new study has found around 40 percent of anti-cancer therapies ushered through the US Food and Drug Administration’s (FDA) accelerated approvals pathway between 2013 and 2017 didn’t show clinical benefit in follow-up trials more than five years on.
Created in response to the HIV/AIDS epidemic of the 1980s and early 1990s, the US FDA’s accelerated approvals program has, since 1992, allowed for the early approval of drugs that treat serious conditions, and fill an unmet medical need.
Accelerated approvals by the FDA are common, especially for cancer therapies. One-third of all oncology drug approvals go through the accelerated approvals pathway, and more than 80 percent of all accelerated approvals are granted for cancer therapies.
However, accelerated approvals rely on surrogate markers of a drug’s effectiveness that are thought to predict clinical benefit, without measuring the benefit directly. Cholesterol levels, for example, are a surrogate marker for heart disease, but what pharmaceutical companies need to show, in post-approval confirmatory trials, is that a newly approved drug prevents death from heart disease.
In cancer trials, showing that patients live longer with a given treatment – referred to as overall survival – is the ideal clinical endpoint. But trials often use a surrogate measure of progression-free survival, which is how long someone lives with their cancer before it gets worse.
Analyzing FDA accelerated approvals of cancer drugs over the past decade, clinician-researchers at the Brigham and Women’s Hospital in Boston extended research that has previously scrutinized the outcomes of the program, which has been criticized for employing 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.
Between 2013 and 2023, 59 cancer drugs were given the provisional tick of approval through the FDA’s accelerated approvals pathway, spread across 129 indications or uses.
Among the 46 drug indications approved between 2013 and 2017, results of confirmatory trials were still outstanding for seven medicines by mid-2023. Meanwhile, 10 drugs had been withdrawn.
But 41 percent – or 19 of the 46 cancer drugs granted accelerated approval in that period – didn’t extend patients’ lives or improve their quality of life, the researchers found.
Add in the seven ongoing trials for which results aren’t yet available, and that figure rises to 57 percent of fast-tracked cancer drugs failing to show benefit five years post-approval.
There are, however, some signs that the system is improving. Fast-tracked drugs that proved to be ineffective in follow-up trials were withdrawn from the approvals process quicker, in only 3.6 years in 2017 down from roughly 10 years in 2013.
Except pharmaceutical companies are taking longer to demonstrate that drugs are effective in mandatory post-approval studies, meaning those drugs are available for years before clinicians – and their patients – can be sure ‘stand-in’ surrogate markers actually reflect clinical benefit.
The researchers found that the time it took for fast-tracked drugs to be granted traditional approval if they did show benefit has dragged out over the study period: increasing from 1.6 years to 3.6 years over the study’s duration.
This parallels other research showing delays in confirmatory trials can result in some drugs being used for more than a decade without confirming that they help patients live longer or better lives.
This is not the only issue plaguing clinical cancer research. A 2022 study found that data from more than half of 300 audited clinical trials from the last decade remained inaccessible despite those trials underpinning anti-cancer drug approvals. That means researchers and clinicians can’t inspect the evidence on which the FDA based its decisions.
But accelerated approvals continue to come under fire, especially in the wake of the FDA’s 2021 decision to approve aducanumab, an antibody for Alzheimer’s disease that cleared protein clumps associated with the disease, but didn’t slow cognitive decline. This year its manufacturer, Biogen, will discontinue aducanumab, citing other priorities.
In June 2022, the US government passed legislative reforms to the accelerated approval pathway, which researchers said were “long overdue”. Those changes will mean the FDA can require that drug companies have at least started confirmatory trials before granting accelerated approvals, and must report on their study progress twice yearly.
Time will tell what impact those reforms will have.
The study has been published in the Journal of the American Medical Association.
