Most of the oncology drugs that received the FDA’s accelerated approval from 2011 to 2020 had some kind of FDA postmarketing safety action, according to a research letter.

Safety actions included warning and precautions, boxed warnings, drug safety communications, and a safety-related withdrawal from the market, and most were not serious, the authors wrote in JAMA Network Open.

Oncology drugs make up more than 80% of accelerated approvals. Part of the accelerated approval process is a requirement that subsequent postmarket studies are conducted to confirm the drug’s benefit. Since previous research has shown drugs receiving accelerated approval tend to have more postmarketing safety actions, the authors conducted a cross-sectional study to look specifically at oncology drugs in more recent years.

Of 52 oncology drugs that received accelerated approval during the study period, 69.2% had an FDA postmarketing safety action, typically around 2 years after their approval, wrote Maryam Mooghali, MD, MSc, of the Yale School of Medicine in New Haven, Connecticut, and her colleagues.

The findings were intriguing but not surprising to Jennifer Litton, MD, chief clinical research officer and professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News.

The study showed diligence from the FDA on continuing to follow data on accelerated approvals, Litton said.

She highlighted the value of the accelerated approval mechanism of the agency in getting patients earlier access to oncology drugs.

This “will be even more important given the rapid number of highly specific drugs being developed that will affect both rare cancers and rare subsets of common cancers,” she said. “Waiting for the trial designs of the past to go through each stage individually may slow down drugs that could be, in some cases, a patient’s best hope.”

She further acknowledged the responsibility that clinicians have in discussing use of accelerated approval drugs with patients.

“Clinicians have a duty to understand why this therapeutic was granted an accelerated approval vs traditional approval and what are the post-accelerated approval requirements,” Litton said. “Clinicians and patients should have candid conversation that this is accelerated approval, including what we know now as well as the unknowns and potential for new safety signals. Clinicians should be diligent in monitoring their patients on these and other therapeutics for side effects” and new symptoms.

“We should not let perfect be the enemy here of new therapies being available for patients who may need them as soon as possible as long as the clinicians and the patients are both well informed,” Litton added.

Methods and Results

The researchers identified all oncology drugs that received accelerated approval from 2011 to 2020 using the Drugs@FDA database and then used the FDA’s Project Confirm to look at which ones were converted to traditional approval or withdrawn. Then they gathered all data on warnings and precautions, boxed warnings, safety communications, safety-related withdrawals, and other FDA postmarketing safety actions for all the drugs through April 30, 2025.

They also assessed whether accelerated approval drugs with postmarketing safety actions later received accelerated approval for supplemental indications, whether the initial accelerated approval for each drug had safety-related postmarketing requirements, and whether examining safety issues was part of accelerated approval postmarketing requirements.

The oncology drugs the researchers assessed included 67.3% small molecule and 32.7% biologics. Most (86.5%) were orphan drugs, nearly half (42.3%) were first-in-class, and 69.2% were designated as breakthrough therapies. Among the postmarketing safety actions recorded, 63.5% were new warnings or precautions, 11.5% were new boxed warnings, 7.7% were drug safety communications, and 3.8% were withdrawn from the market due to safety. It took a median 2.2 years from accelerated approval until the first safety action occurred.

All but one of the 13 drugs (92.3%) with postmarketing safety analyses requirements had postmarketing safety actions compared with 61.5% of the other drugs without a safety analysis requirement (P = .04).

When looking more broadly at drugs that had any kind of safety-related postmarketing requirement, however, there was no difference in the proportion of safety actions between those with a safety-related requirement (76.3%) and those without one (50%; P = .09). A quarter (25%) of the drugs that had a safety action subsequently received accelerated approval for additional indications.

The researchers acknowledged that their analysis was limited by lack of comparison group of oncology drugs that received traditional approval and the need to rely on publicly available data.

Although the FDA’s current surveillance systems “detect many safety concerns, our findings underscore the need to strengthen safety monitoring alongside efforts to confirm clinical benefit to improve accelerated approval program, particularly considering their uncertain efficacy and vulnerability of the target population,” the authors concluded.

Other Challenges to Drug Development and Success

Litton noted challenges of keeping up with the rapid pace of drug evaluation in current clinical trials and the need for these trial designs to evolve accordingly.

“Often, for phase 3 registrational trials, the standard-of-care comparison arm may become obsolete before the trial even completes enrollment,” Litton said. “I suspect we will see more real-world evidence and post-approval toxicity monitoring. This can be improved with the help of widespread use of electronic health records and direct data collection from trial participants.”

The authors called for most serious safety actions to be “interpreted amid uncertain benefit, as many oncology drugs granted accelerated approval lack confirmation of clinical benefit even after conversion to traditional approval.”

“Drugs with safety analyses as part of their accelerated approval postmarketing requirements had higher rates of safety actions, suggesting that proactive surveillance may facilitate harm detection, particularly given the small sample size and short follow-up of pivotal studies supporting accelerated approvals,” they noted.

The research was funded by Arnold Ventures to the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency. Mooghali reported having no disclosures. Coauthors reported receiving a variety of research grants from federal entities, including the FDA, that were unrelated to the study and consulting fees from law firms or serving as an expert witness in court cases which were unrelated to this research. One author also reported receiving a research grant from Johnson & Johnson. Litton reported having no disclosures.

Tara Haelle is a science/health journalist based in Dallas.