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 The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

in response to a New Drug Application, Amended New Drug Application or

Biologics License Application A biologics license application (BLA) is defined by the U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is respo ...

, indicating that the application will not be approved in its present form. CRLs replaced approvable letters in 2018.

Background

Under the

Prescription Drug User Fee Act The ''Prescription Drug User Fee Act'' (PDUFA) was a law passed by the United States Congress in 1992 which allowed the Food and Drug Administration (FDA) to collect fees from drug manufacturers to fund the new drug approval process. The Act prov ...

, the

has a limited timespan (known as the PDUFA date) to decide a New Drug Application, Amended New Drug Application or

. The FDA may either approve the application or issue a Complete Response Letter. Grounds behind issuing a CRL may include

labelling Labelling or using a label is describing someone or something in a word or short phrase. For example, the label "criminal" may be used to describe someone who has broken a law. Labelling theory is a theory in sociology which ascribes labelling ...

issues,

current Good Manufacturing Practice Current good manufacturing practices (cGMP) are those conforming to the guidelines recommended by relevant agencies. Those agencies control the authorization and licensing of the manufacture and sale of food and beverages, cosmetics, pharmaceutica ...

concerns or concerns about the safety or effectiveness of the drug. A sponsor receiving CRL may withdraw the application, request a hearing or resubmit the application. Because hearings are open to the public, this course of action is relatively rarely chosen.

Class 1 and Class 2 resubmissions after CRLs

MAPP 6020 Rev. 2, the

policy manual governing resubmissions following a CRL, classifies CRLs as requiring a Class 1 or Class 2 resubmission. Where a sponsor decides to submit a response to a CRL, the response is classified within 30 days, if the response is complete. A Class 1 response typically denotes minor amendments, such as

, 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. A Class 1 response is typically handled within 3 months, while a Class 2 response is typically handled within 6 months.

Economic impact

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

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, forcing the company to restructure.

BioMarin Pharmaceutical BioMarin Pharmaceutical Inc. is an American biotechnology company headquartered in San Rafael, California. It has offices and facilities in the United States, South America, Asia, and Europe. BioMarin's core business and research is in enzyme re ...

lost over 30% of its value when a CRL was issued in respect of its

hemophilia A Haemophilia A (or hemophilia A) is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males. In the majority of cases it is inherited as an X-linked recessive trait, though there are cases which aris ...

gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human D ...

, valoctocogene roxaparvovec. Sesen Bio's stock price dropped over 80% after reporting a CRL for Vicineum as a treatment for a type of bladder cancer.

Disclosure

Typically, CRLs are not disclosed publicly as they often include proprietary information. Press releases, when issued, typically do not include most of the details contained in the CRL, including the reasons behind it. While there is no general obligation to publicly disclose a CRL's existence or contents, the

U.S. Securities and Exchange Commission The U.S. Securities and Exchange Commission (SEC) is an independent agency of the United States federal government, created in the aftermath of the Wall Street Crash of 1929. The primary purpose of the SEC is to enforce the law against market ...

has in the past brought action against companies that allegedly misled investors about a CRL.{{Cite web, title=SEC.gov {{! FCPA, Disclosure, and Internal Controls Issues Arising in the Pharmaceutical Industry, url=https://www.sec.gov/news/speech/2015-spch030315ajc.html#.VPcThIe2H-o, access-date=2021-06-30, website=www.sec.gov

References

Food and Drug Administration Regulation Pharmaceutical industry Pharmaceutical regulation in the United States