A comprehensive analysis of cancer drugs approved through the FDA's accelerated approval pathway reveals significant gaps between regulatory approval and demonstrated clinical benefit, according to research published in the Journal of the American Medical Association and presented at the American Association for Cancer Research Annual Meeting 2024.
The study examined 46 cancer drugs granted accelerated approval between 2013 and 2017, finding that only 43% demonstrated clinical benefit in confirmatory trials after more than five years of follow-up. Despite this limited evidence, 63% of these drugs were converted to regular approval, raising questions about regulatory standards and patient safety.
Accelerated Approval Program Under Scrutiny
The FDA's accelerated approval program, established more than 30 years ago, was designed to provide early access to drugs treating serious conditions with unmet medical needs. Originally created in 1992 to speed access to HIV drugs, today 85% of accelerated approvals go to cancer drugs.
"Five years after the initial accelerated approval, you should have a definitive answer," said Dr. Ezekiel Emanuel, a cancer specialist and bioethicist at the University of Pennsylvania who was not involved in the research. "Thousands of people are getting those drugs. That seems a mistake if we don't know whether they work or not."
The program allows the FDA to grant early approval based on surrogate endpoints—markers thought to predict clinical benefit but not themselves measures of clinical benefit. Drug companies are expected to conduct rigorous follow-up testing to confirm anticipated benefits.
Key Findings Reveal Regulatory Gaps
The research team, led by Ian T. T. Liu from Harvard Medical School's Program On Regulation, Therapeutics And Law (PORTAL), conducted two comprehensive analyses. The first focused on drugs with more than five years for confirmatory trials, while the second examined conversion evidence for all drugs approved between 2013-2023.
Among the 46 drugs with sufficient follow-up time, 63% were converted to regular approval, 22% were withdrawn, and 15% remained ongoing after a median of 6.3 years. The study found that conversion decisions increasingly relied on limited evidence, with only 40% based on overall survival data.
"We found seven drugs that were converted to regular approval based on response rate, i.e., tumor shrinkage, but this leaves a great deal of uncertainty regarding whether the drugs ultimately benefit patients," said study co-author Dr. Edward Cliff of Harvard Medical School.
Changing Timeline Patterns
The research revealed evolving patterns in regulatory decision-making. The time to regular approval conversion increased from 1.6 to 3.6 years, while the time to drug withdrawal decreased from 9.9 to 3.6 years.
"Faster, appropriate withdrawal decisions are a good thing for patients, as they ensure that ineffective drugs are on the market for a shorter period of time," Liu explained. However, he emphasized that conversion decisions should be both timely and supported by high-quality clinical outcomes.
Patient Communication Concerns
The study raises important questions about patient understanding of accelerated approval drugs. "It's unclear how much cancer patients understand about drugs with accelerated approval," said study co-author Dr. Edward Cliff. "We raise the question: Is that uncertainty being conveyed to patients?"
Dr. Jennifer Litton of MD Anderson Cancer Center, who was not involved in the study, noted that accelerated approval drugs may be the only option for patients with rare or advanced cancers. She emphasized the importance of careful communication: "You can provide the data you have, but you shouldn't overpromise."
Regulatory Response and Future Implications
Congress recently updated the accelerated approval program, giving the FDA more authority and streamlining the withdrawal process. The changes allow the agency "to withdraw approval for a drug approved under accelerated approval, when appropriate, more quickly," according to FDA spokesperson Cherie Duvall-Jones.
The FDA can now require confirmatory trials to be underway when granting preliminary approval, potentially speeding verification of drug effectiveness.
Research Implications
The findings highlight the need for improved surrogate endpoint validation and more stringent evidence requirements. The researchers examined 129 drugs granted accelerated approval for cancer indications from 2013-2023, with 48 converted to regular approval during this period.
"We hope these findings will encourage greater communication between patients and physicians about the uncertainty surrounding cancer drugs approved on preliminary surrogate measures," Liu said. The research also calls for regulators to scrutinize the practice of converting accelerated approvals based on limited evidence and invest in robust validation of oncology surrogate measures.
The study was funded by Arnold Ventures, with researchers reporting no conflicts of interest.
