Complete Response Letter (CRL)
A communication from the FDA indicating that the review of an application is complete but the agency has identified issues that must be resolved before approval can be granted. CRLs specify the deficiencies and may require additional data, studies, or manufacturing changes.
Technical Context
A CRL indicates that the FDA has completed its review and cannot approve the application in its current form. CRLs identify specific deficiencies that must be addressed — these can be: clinical (insufficient efficacy evidence, unresolved safety concerns, inadequate study design), manufacturing (cGMP violations at manufacturing facility, inadequate process validation, stability concerns), labelling (unacceptable proposed labelling), or administrative. The sponsor has three options: resubmit with the requested information (Class 1 resubmission — 2-month review for minor issues; Class 2 — 6-month review for major issues), request a meeting with the FDA to discuss the path forward, or withdraw the application. CRLs are not publicly disclosed by the FDA (though companies often announce them). For peptide drugs, CRLs have been issued for manufacturing quality concerns, requests for additional clinical data, and facility inspection findings.