Deficiencies in oncology marketing applications leading to FDA rejections: An assessment of complete response letters.

Abstract

e23048 Background: The U.S. Food and Drug Administration (FDA) issues Complete Response Letters (CRLs) to notify sponsors of the agency’s decision not to approve drug marketing applications. The CRL describes the deficiencies in drug development that justified FDA’s decision. Until recently, CRLs were not publicly available. In 2025, FDA published CRLs of marketing applications submitted between 2020 and 2024, including those that were approved later. We reviewed oncology-related CRLs to assess the deficiencies impacting approvals of anti-cancer drugs. Methods: We identified oncology-related CRLs for original and supplement New Drug Applications (NDAs) and Biologics License Applications (BLAs). From each CRL, we extracted data on drug indications; CRL date; and the deficiencies that justified FDA’s decisions, categorized as: Chemistry, Manufacturing, and Controls (CMC); manufacturing facilities; clinical inspections; non-clinical; clinical pharmacology; microbiology; trial design; clinical efficacy; and clinical safety. We consulted the Drugs@FDA website to identify applications that were approved later, with respective approval dates. For unapproved applications, we consulted the sponsors’ website to supplement information not available in the CRL. We descriptively report the proportion of CRLs citing each deficiency type. For applications that were later approved, we report the time intervals from CRL date to approval date. Results: Of 45 oncology-related CRLs (25 for NDAs and 20 for BLAs); 24 (53%) addressed single tumor types; and 18 (40%) addressed monotherapy indications. The number and proportion of CRLs with each deficiency type were: manufacturing facilities (33, 73%); CMC (28, 62%); clinical efficacy (8, 18%); clinical pharmacology (7, 16%); clinical safety (6, 13%); trial design and microbiology (5, 11% each); clinical inspections (4, 9%); and non-clinical (3, 7%). Of the 28 (62%) applications that were approved later, the median time from CRL to approval was 22.8 months (IQR: 30.6). The table reports the median times to approval based on deficiency type. Conclusions: Manufacturing deficiencies were the most common reasons for FDA’s rejections of oncology marketing applications. Deficiencies leading to CRLs are associated with substantial delays in time to market, with clinical efficacy and safety deficiencies leading to potentially longer delays. The findings highlight the value of risk mitigating strategies in specific areas of drug development. Time to approval from receipt of CRL (N=28). Deficiency Type Median (range), months Manufacturing Facility (n=20) 16.8 (8.6, 120.8) CMC (n=21) 18.2 (8.6, 120.8) Clinical Pharmacology (n=6) 21.6 (8.6, 120.8) Microbiology (n=3) 24.9 (15.4, 35.3) Trial Design (n=4) 30.3 (15.3, 120.8) Clinical Efficacy (n=7) 39.6 (9.1, 120.8) Clinical Safety (n=4) 56.3 (9.1, 120.8) Any Deficiency (n=28) 22.8 (8.6, 120.8)