In 1992, the U.S. Food and Drug Administration (FDA) instituted the Accelerated Approval regulations, which allow drugs that treat serious conditions, including cancer, and fill an unmet need to be approved early based on a surrogate endpoint.1 However, any drug approved under this pathway is still required to undergo additional studies to confirm its anticipated clinical benefit.
Ian T.T. Liu, MD, JD, MS, MPH, and colleagues investigated whether cancer drugs granted accelerated approval by the FDA ultimately demonstrated clinical benefit. Dr. Liu is 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. Edward Cliff, MBBS, MPH, also with Brigham and Women’s Hospital and Harvard Medical School, is the senior study author.
Edward Cliff, MBBS, MPH
The investigators found that just 43% of the drugs showed benefit in overall survival or quality of life within 5 years of accelerated approval in confirmatory trials.2 The study authors indicated that patients should be clearly informed about these findings. The study results were presented at the American Association for Cancer Research (AACR) Annual Meeting 2024.2
Study Methodology and Results
The researchers conducted two analyses. The first focused on all drugs granted FDA accelerated approval from 2013 to 2017 with 5 years of follow-up confirmatory trials. The second analysis 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 timeframe. Pertinent information from the trials, including National Clinical Trial number, trial design, primary endpoint, and primary and secondary outcomes, was used to evaluate clinical benefit.
The researchers found that 129 cancer drug–indication pairs were granted accelerated approval from 2013 to 2023. Among 46 indications with more than 5 years of follow-up (approved 2013–2017), two-thirds (n = 29, 63%) were converted to regular approval, 10 (22%) were withdrawn, and 7 (15%) remained ongoing after a median of 6.3 years.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 (n = 20, 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 cancer 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, and 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 Dr. Liu in a statement. “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.”
DISCLOSURE: Funding for this study was provided by Arnold Ventures. Dr. Liu and Dr. Cliff reported no conflicts of interest.
REFERENCES
1. U.S. Food & Drug Administration: Accelerated Approval. Available at www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval#:~:text=Mindful%20of%20the%20fact%20that,based%20on%20a%20surrogate%20endpoint. Accessed April 26, 2024.
2. Liu ITT, Kesselheim AS, Cliff ERS: Clinical benefit and regulatory outcomes of cancer drugs receiving accelerated approval. AACR Annual Meeting 2024. Poster 918. Presented April 7, 2024.
