P108: Barriers to Regulatory Approval: Insights from Recently Released FDA Complete Response Letters
Poster Presenter
Cynthia Guanga
Undergraduate Research Assistant
University of Southern California United States
Objectives
To analyze trends in FDA Complete Response Letters (CRLs) and identify commonly cited deficiencies that contribute to regulatory non-approval decisions.
Method
Complete Response Letters (CRLs) were downloaded from Open FDA on December 10, 2025, at 1:00 PM PST and stored in a shared repository. Two independent reviewers evaluated each CRL and recorded identified deficiencies. Discrepancies were resolved through reconciliation to produce a finalized dataset.
Results
This analysis found that the most cited deficiencies in FDA Complete Response Letters (CRLs) were related to Chemistry, Manufacturing, and Controls (CMC), efficacy, labeling, and safety. CMC deficiencies were the most common, appearing in 58% of CRLs. Efficacy deficiencies appeared in 27%, labeling in 26%, and safety in 24% of CRLs. CMC deficiencies were also more common in Biologics License Applications (BLAs), with facility inspection failures representing the most frequent CMC issue.
Conclusion
A data-driven evaluation of FDA regulatory review trends for New Drug Applications (NDAs) and Biologics License Applications (BLAs) highlights the significant role that Chemistry, Manufacturing, and Controls (CMC) deficiencies play in the issuance of Complete Response Letters (CRLs). Among the reviewed CRLs, CMC-related issues were frequently cited, pointing to the importance of robust manufacturing processes, comprehensive quality controls, and well-documented production data in supporting successful regulatory submissions. These findings suggest that proactive attention to CMC strategy during early development and throughout the product lifecycle may help mitigate regulatory risk and reduce the likelihood of approval delays. Strengthening CMC readiness prior to submission—including early engagement with regulatory agencies, thorough validation of manufacturing processes, and clear documentation of product quality attributes—may prevent common deficiencies before regulatory review. The findings also highlight the value of greater transparency in CRL communications. While the FDA has increasingly released CRLs in recent years, many remain limited in detail or are not publicly disclosed. Enhanced transparency regarding the nature and frequency of cited deficiencies could provide valuable learning opportunities for sponsors, researchers, and regulatory professionals. A better understanding of recurring regulatory concerns may allow stakeholders to anticipate potential challenges, refine development strategies, and improve the quality of future submissions. Systematic analysis of CRLs can provide meaningful insight into FDA review patterns and the factors most associated with non-approval decisions. Ultimately, these insights may support more efficient regulatory pathways, increase the likelihood of successful approvals, and accelerate patient access to safe and effective innovative therapies.
