Accelerated approvals for cancer drugs is a good idea in theory. This US Food and Drug Administration (FDA) pathway allows promising new cancer agents to reach the market, and patients, sooner.
But speed can come at a price.
The bargain the FDA has struck with manufacturers is companies can use less robust metrics — surrogate markers — to get their drugs to market earlier. These markers, which typically track how well a drug shrinks a tumor or halts tumor growth, act as a temporary stand-in for the ultimate goals — better overall survival and quality of life.
In exchange, manufacturers agree to run confirmatory trials following an FDA approval to determine whether the new drug or regimen does indeed reach either of those core goals.
However, a growing body of evidence suggests that these surrogate markers don't necessarily predict better overall survival or quality of life.
The accelerated approval system does not always work very well, said Bishal Gyawali, MD, PhD, a Medscape Medical News contributor and an associate professor from Queen's University, Kingston, Ontario, Canada. Confirmatory trials can take years to conduct, and when manufacturers do complete them, the drugs often fail to demonstrate a clinical benefit.
A recent study, for instance, found that 26 of 46 cancer drug indications (57%) granted accelerated approvals between 2013 and 2017 failed to demonstrate a clinical benefit after at least 5 years of follow-up data. In that time, 10 of the 46 indications (22%) were withdrawn.
When Gyawali and colleagues published findings from a similar analysis 5 years earlier, he reported worse outcomes in confirmatory trials. The investigation, which explored 93 cancer drug indications that received accelerated approval from December 1992 through the end of May 2017, revealed that only 20% demonstrated improvements in overall survival in follow-up confirmatory analyses.
Still, the accelerated approval pathway has become a common mechanism to get drugs to patients in the United States sooner.
"It's the right thing, especially for the metastatic patient community, to have these drugs accessible," said Julie R. Gralow, MD, American Society of Clinical Oncology's chief medical officer. "For metastatic patients, where for the most part we don't have cures, we can be a little bit more liberal vs in the early-stage setting, when there are very high cure rates…we have to be more cautious."
Ian T.T. Liu, MD, JD, MPH, agreed that the accelerated pathway makes sense in the metastatic setting, where there are fewer options for patients, but researchers also use this process more broadly, largely because the evidence required for an FDA approval is much "easier to produce."
Accelerated approvals often use progression-free or disease-free survival as surrogate endpoints. Progression-free survival is a common surrogate endpoint for overall survival in cancer drug trials, and one of the more reasonable surrogates, noted Liu, of Brigham and Women's Hospital and Harvard Medical School, Boston.
But research suggests that the correlation between progression-free and overall survival can be weak.
Progression-free survival still "leaves a substantial amount of uncertainty as to a drug's ultimate benefit," Liu said.
What's more concerning, Liu noted, is in recent years, seven oncology drugs have been converted from accelerated to full approvals based solely on an overall response rate to the drug — a much weaker surrogate endpoint that looks only at tumor growth, shrinkage, or markers in the blood.
"That's even more problematic from our perspective because the response rate doesn't measure toxicity," Liu continued. "If you give a cancer drug to a patient with cancer and it poisons the cancer, but it is also poisoning the patient, you might be inducing tumor shrinkage, but it might not be at a cost that a patient would be willing to bear."
Accelerated and full approvals based on overall response rates signal that the FDA has adopted a "deliberate policy of saying that we are going to lower the threshold for approval [and] approve drugs that have a chance of being beneficial," said Nathan I. Cherny, MD, director of Cancer Pain and Palliative Care Service, Shaare Zedek Medical Center, Jerusalem, Israel. "They are essentially prioritizing availability over uncertainty."
Clinical trials can also be designed in ways that favor the investigational drug. The control arm, for instance, may not receive a fair comparator regimen, such as a current standard of care. Such designs may make the investigational drug seem stronger before it's approved, and that apparent benefit may then dissipate when the new regimen is studied in a real-world population.
Another issue: When it comes to completing, or even starting, confirmatory trials, drug companies may drag their feet, Liu noted.
"There was a problem for a long time where companies were not conducting their confirmatory trials in a timely manner," Liu said. "It could be 10 years after the initial accelerated approval, and these drugs would still be on the market."
But the FDA "received new powers in 2022 to require that a confirmatory trial already be enrolling patients at the time accelerated approval was given," he added.
The FDA has also proposed using the same trial to provide evidence for accelerated approvals and for full approvals, meaning the trial can expand and enroll more patients, and gather more data to confirm clinical benefit. "I think is a reasonable midway approach," Gyawali said.
Overall, the goal should not be to do away with the accelerated approval process because it sometimes does deliver powerful agents to patients quickly. What's key, Edward Cliff, MBBS, MPH, told Medscape Medical News earlier this year, is to "keep the speed while getting certainty around clinical benefits" with robust and timely confirmatory trials.
In the meantime, "clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies," explained Cliff, a hematology trainee at Brigham and Women's Hospital, Boston, and a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia. "It's important for them to have the information."