The accelerated approval program of the U.S. Food and Drug Administration (FDA) allows certain medications to be marketed if they are indicated for serious disease and there has been preliminary evidence of the drug’s efficacy. Pharmaceutical companies must then conduct postapproval trials to confirm the medication’s clinical benefit. If the postapproval trial fails, the indication should be removed from the product’s label. Some of these medications can remain available if they have other approved indications and may continue to be prescribed “off-label” for the withdrawn indication.
Hwang et al performed a cohort study to investigate changes in cancer drug use following accelerated approval of three medications for four indications after publication of negative confirmatory trials. Results of the study were published as a research letter in JAMA Oncology.
Study Details
The authors identified three cancer medications that had their accelerated approval withdrawn for four indications from January 2020 to December 2022, but each drug remained on the market for at least one other approved indication. The medications were atezolizumab (breast cancer and urothelial cancer), idelalisib (follicular lymphoma), and romidepsin (peripheral T-cell lymphoma). The study included 762,752 patients, grouped into four cohorts: breast cancer, urothelial cancer, follicular lymphoma, and peripheral T-cell lymphoma. Changes were measured in the monthly proportion of incident (no use in the prior 365 days) and prevalent medication use following the first public reporting of negative trial results.
The investigators reported that findings showed that the use of medications in the four groups increased following accelerated approval and before any negative results were reported from postapproval studies. Once the confirmatory studies published negative findings, however, use of these medications decreased significantly despite ongoing availability of the medications.
According to investigators, the use of atezolizumab, for example, increased by 16 patients per 1 million patients (95% confidence interval [CI] = 12 to 21 patients/million) with breast cancer before the negative confirmatory findings were published; following publication of negative findings, use of atezolizumab decreased by 28 patients per million (95% CI = –35 to –20).
The time between accelerated approval and negative confirmatory trial results were published varied, ranging from 12 to 113 months; further, the time between publication of the negative trial and withdrawal of FDA approval also varied, in some cases substantially, ranging from 1 to 47 months.
Conclusions
The authors concluded, “Ensuring timely completion of postapproval studies and enforcing appropriate regulatory actions based on negative trial results is necessary to minimize patient exposure to ineffective and potentially unsafe medications.”
Catherine S. Hwang, MD, MSPH, of the Division of General Internal Medicine and Geriatrics, Oregon Health and Science University, is the corresponding author of the study.
Disclosure: For full disclosure of all study authors, visit JAMA.org.
