Complete Response Letter

In United States pharmaceutical regulatory practice, a Complete Response Letter (CRL), or more rarely, a 314.110 letter, is a regulatory action by the Food and Drug Administration in response to a New Drug Application, Amended New Drug Application or Biologics License Application, indicating that the application will not be approved in its present form.^[1] CRLs replaced approvable letters in 2018.

Under the Prescription Drug User Fee Act, the Food and Drug Administration has a limited timespan (known as the PDUFA date) to decide a New Drug Application, Abbreviated New Drug Application or Biologics License Application. The FDA may either approve the application or issue a Complete Response Letter.^[2] Grounds behind issuing a CRL may include labeling issues, current Good Manufacturing Practice concerns or concerns about the safety or effectiveness of the drug.^[3]

A sponsor receiving CRL may withdraw the application, request a hearing or resubmit the application.^[1] Because hearings are open to the public, this course of action is relatively rarely chosen.^[4]

MAPP 6020 Rev. 2, the Food and Drug Administration policy manual governing resubmissions following a CRL, classifies CRLs as requiring a Class 1 or Class 2 resubmission.^[5] Where a sponsor decides to submit a response to a CRL, the response is classified within 30 days, if the response is complete.^[6] A Class 1 response typically denotes minor amendments, such as labeling, assay validation data or minor re-analysis of the data supporting the application, while a Class 2 response typically involves more extensive concerns and/or a reinspection.^[6] A Class 1 response is typically handled within 3 months, while a Class 2 response is typically handled within 6 months.^[5]

A CRL frequently has a significant impact on the sponsor's share price. Orphazyme, a Danish biopharmaceutical company, lost over half of its share value overnight upon disclosing a CRL for arimoclomol, a proposed treatment for Niemann–Pick disease, type C,^[7] forcing the company to restructure.^[8] BioMarin Pharmaceutical lost over 30% of its value when a CRL was issued in respect of its hemophilia A gene therapy, valoctocogene roxaparvovec.^[9] Sesen Bio's stock price dropped over 80% after reporting a CRL for Vicineum as a treatment for a type of bladder cancer.^[10]

Typically, CRLs are not disclosed publicly as they often include proprietary information.^[11] Press releases, when issued, typically do not include most of the details contained in the CRL, including the reasons behind it.^[12] While there is no general obligation to publicly disclose a CRL's existence or contents, the U.S. Securities and Exchange Commission has in the past brought action against companies that allegedly misled investors about a CRL.^[13]