In 1992, the U.S. Food and Drug Administration (FDA) instituted its Accelerated Approval regulations, which allow drugs that treat serious conditions and fill an unmet need to be approved early based on a surrogate endpoint. However, any drug approved under this pathway is still required to undergo additional studies to confirm its anticipated clinical benefit.

A study by Liu et al presented at the American Association for Cancer Research (AACR) Annual Meeting 2024 (Abstract 918) investigating whether cancer drugs granted accelerated approval by the FDA ultimately demonstrated clinical benefit has found that only 43% of the drugs showed benefit in terms of overall survival or quality of life within 5 years of accelerated approval in confirmatory trials. Patients should be clearly informed about the many cancer drugs that use the accelerated approval process—and that do not show benefits in patient-centered clinical outcomes—concluded the study authors.

Study Methodology

The researchers conducted two analyses: the first focused on all drugs granted FDA accelerated approval from 2013 to 2017 with 5-year follow-up confirmatory trials; the second examined the evidence used to convert accelerated approvals to regular approvals for all drugs between 2013 and 2023, even if they had less than 5 years to evaluate their efficacy in clinical trials. The researchers used publicly available FDA data to identify cancer drugs granted accelerated approval during that time frame. Pertinent information from the trials, including National Clinical Trial number, trial design, primary endpoint, and primary and secondary outcomes, were used to evaluate clinical benefit.

Results

The researchers found that 129 cancer drug-indication pairs were granted accelerated approval from 2013 to 2023. Among 46 indications with > 5 years follow-up (approved 2013–2017), two-thirds (29 of 46, 63%) were converted to regular approval, 10 (22%) were withdrawn, and 7 (15%) remained ongoing after a median of 6.3 years. Fewer than half (20 of 46, 43%) demonstrated a clinical benefit in confirmatory trials.

Time to withdrawal decreased from 9.9 to 3.6 years, and time to regular approval increased from 1.6 to 3.6 years. Among 48 drug-indication pairs converted to regular approval, 19 (40%) were converted based on overall survival, 21 (44%) on progression-free survival, 5 (10%) on response rate plus duration of response, 2 (4%) on response rate, and 1 despite a negative confirmatory trial. Comparing accelerated and regular approval indications, 18 (38%) were unchanged while 30 (63%) had different indications.

“Most cancer drugs granted accelerated approval did not demonstrate benefit in overall survival or quality of life within 5 years of accelerated approval. Patients should be clearly informed about the many cancer drugs that use the accelerated pathway and do not end up showing benefits in patient-centered clinical outcomes,” concluded the study authors.

Clinical Significance

“We hope these findings will encourage greater communication between patients and physicians about the uncertainty surrounding cancer drugs approved on preliminary surrogate measures and the potential risks and benefits of a given treatment,” said first study author Ian T.T. Liu, MD, JD, MPH, MS, a postdoctoral research fellow with the Program On Regulation, Therapeutics And Law (PORTAL) within the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School.

“Our findings may also encourage regulators to scrutinize the commonplace practice of converting accelerated to regular approvals based on limited evidence, to invest resources in robustly validating more oncology surrogate measures, and to ensure that confirmatory trials will all be powered to show improvements in endpoints that matter to patients and their families, such as overall survival and quality-of-life measures,” he added.

Disclosure: Funding for this study was provided by Arnold Ventures. For full disclosures of the study authors, visit abstractsonline.com.