The US Food and Drug Administration (FDA) developed the accelerated approval pathway in response to the HIV epidemic of the 1980s, to bring promising drugs treating unmet medical needs to the market sooner. After accelerated approval is granted, confirmatory studies are required to determine clinical benefits and regulatory outcomes. In oncology, most accelerated approvals are granted on the basis of surrogate measures such as tumor response rate and progression-free survival, and the FDA has increasingly used these measures to support conversion from accelerated to regular approval. Drugs granted accelerated approval are often incorporated into guidelines and covered by insurance providers even before evidence confirms clinical benefit, resulting in patient exposure to higher out-of-pocket costs for drugs that do not always achieve their expected benefits.
In an article recently published in JAMA, Dr Ian Liu and colleagues evaluated cancer accelerated approval indications from 2013 to 2023 to determine whether cancer drugs granted accelerated approval ultimately demonstrate clinical benefit, and to evaluate the basis of conversion to regular approval. They found that many cancer drugs granted accelerated approval did not demonstrate clinical benefit, defined as improvement in overall survival or quality of life within 5 years of accelerated approval. The first analysis of indications with at least 5 years of follow-up showed that about two-thirds were converted to regular approval, 22% were withdrawn, and 15% remained without a definitive outcome. Of those converted to regular approval, only two-thirds demonstrated clinical benefit and 31% were converted without showing a benefit in either overall survival or quality of life in confirmatory trials. The time from initial approval to projected confirmatory trial completion increased from 3.4 years in 2013 to 4.5 years in 2017, and duration from accelerated approval to conversion to regular approval increased from 1.6 years to 3.6 years for converted indications. Most conversions to full approval occurred in 1 to 2 years, and withdrawals occurred between 1 and 5 years.
The second cohort focused on conversion decisions and found that 38% of drug-indication pairs had the same indication for accelerated and regular approval, 38% included an earlier line of therapy, 17% were broadened, and 6% were narrowed. Of those converted, 40% were converted on the basis of pivotal trials demonstrating improvement in overall survival, while 1 was converted despite a negative confirmatory trial. The rest were based on improvement in progression-free, event-free, or disease-free survival; response rate plus duration of response; or, after 2021, response rate. Since 2021, 37% of conversions were based on response rate.
High level
Determining clinical benefit before conversion from accelerated to regular approval is important because it is more difficult for the FDA to seek withdrawal of an indication after regular approval. With little difference in patient access between accelerated and regular approvals, confirmatory trials to determine clinical benefits and regulatory outcomes can be conducted without compromising treatment availability. In addition to establishing clinical benefit, confirmatory trials should also identify the population for which a drug is most effective. Reducing the time from accelerated approval to completion of confirmatory trials is important to support conversion decisions, but manufacturers have a responsibility to provide superior data with meaningful clinical endpoints to support these decisions. Additionally, confirmatory trial designs should include appropriate comparisons within the same indication for accelerated and regular approval.
Ground level
Accelerated approval can be useful especially when treatments address a high unmet medical need, but clinicians must be aware when prescribing them that some do not ultimately demonstrate benefit in extending patients’ lives or improving their quality of life. Patients need to be clearly informed about the meaning of accelerated approval and potential for discrepancies between clinical benefits and regulatory outcomes when making treatment decisions.
