Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval

Abstract

Importance: The US Food and Drug Administration's (FDA) accelerated approval pathway allows approval of investigational drugs treating unmet medical needs based on changes to surrogate measures considered "reasonably likely" to predict clinical benefit. Postapproval clinical trials are then required to confirm whether these drugs offer clinical benefit.

Objective: To determine whether cancer drugs granted accelerated approval ultimately demonstrate clinical benefit and to evaluate the basis of conversion to regular approval.

Design, setting, and participants: In this cohort study, publicly available FDA data were used to identify cancer drugs granted accelerated approval from 2013 to 2023.

Main outcomes and measures: Demonstrated improvement in quality of life or overall survival in accelerated approvals with more than 5 years of follow-up, as well as confirmatory trial end points and time to conversion for drug-indication pairs converted to regular approval.

Results: A total of 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of follow-up (approved 2013-2017), approximately two-thirds (29, 63%) were converted to regular approval, 10 (22%) were withdrawn, and 7 (15%) remained ongoing after a median of 6.3 years.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 (20/46, 43%) demonstrated a clinical benefit in confirmatory trials. Time to withdrawal decreased from 9.9 years to 3.6 years, and time to regular approval increased from 1.6 years 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 (2%) despite a negative confirmatory trial. Comparing accelerated and regular approval indications, 18 of 48 (38%) were unchanged, while 30 of 48 (63%) had different indications (eg, earlier line of therapy).

Conclusions and relevance: 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 cancer drugs that use the accelerated approval pathway and do not end up showing benefits in patient-centered clinical outcomes.

Figure 1.. Oncology Drugs Granted Accelerated Approval From 2013 to 2023, and Regulatory Outcomes

Oncology drugs granted accelerated approval and regulatory outcome, based on follow-up time.

Figure 2.. Cancer Drugs Granted Accelerated Approval From January 2013 to May 2017

This figure excludes ongoing accelerated approvals with less than 5 years of follow-up (n = 74). Drug (year of accelerated approval) indicates accelerated approval indication. ALL indicates acute lymphoblastic leukemia; cHL, classical Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; ER, estrogen receptor; FL, follicular lymphoma; MCL, mantle cell lymphoma; MM, multiple myeloma; MZL, marginal zone lymphoma; NSCLC, non–small cell lung cancer; PD-L1, programmed cell death ligand 1; PTCL, peripheral T-cell lymphoma; SCC, squamous cell carcinoma; and SLL, small lymphocytic lymphoma. ^aWithdrawn drugs are represented by the lighter bars ending prior to the cutoff date of August 1, 2023.

Figure 3.. Cancer Drugs Granted Accelerated Approval Since 2017

This figure excludes ongoing accelerated approvals with less than 5 years of follow-up (n = 74). Drug (year of accelerated approval) indicates accelerated approval indication. ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; BCC, basal cell carcinoma; CML, chronic myeloid leukemia; DLBCL, diffuse large B-cell lymphoma; dMMR, mismatch repair deficient; FL, follicular lymphoma; GEJ, gastroesophageal junction; HCC, hepatocellular carcinoma; MCL, mantle cell lymphoma; MM, multiple myeloma; MSI-H, microsatellite instability high; MZL, marginal zone lymphoma; NSCLC, non–small cell lung cancer; PD-L1, programmed cell death ligand 1; SCLC, small cell lung cancer; and TNBC, triple-negative breast cancer. ^aWithdrawn drugs are represented by the lighter bars ending prior to the cutoff date of August 1, 2023.