Complete Response Letter

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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.

Background

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, Amended 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 labelling 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]

Class 1 and Class 2 resubmissions after CRLs

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 labelling, 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]

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 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]

Disclosure

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]

References

  1. ^ a b "21 CFR 314.110". www.accessdata.fda.gov. Retrieved 2021-06-30.
  2. ^ Thayer, Ann M. (15 May 2017). "The complete response letter: The mail no one wants to receive". ACS C&EN. Retrieved 2021-06-30.
  3. ^ Chandanais, Ryan (8 December 2017). "Complete Response Letters: What Drug Manufacturers Hope to Avoid". Pharmacy Times. Retrieved 2021-06-30.
  4. ^ "FDA Complete Response Letters: The design v. reality of FDA's responses to drug applications". Healthcare Law Insights. 2015-01-12. Retrieved 2021-06-30.
  5. ^ a b "MAPP 6020.5 Rev. 2: Classifying Resubmissions of original NDAs, BLAs and Efficacy Cupplements in Response to Complete Response Letters". Food and Drug Administration, Center for Drug Evaluation and Research. Retrieved 2021-06-30.
  6. ^ a b "MAPPing Out The Timing Of A Complete Response Submission". Camargo. 27 February 2015. Retrieved 2021-06-30.
  7. ^ Kilgore, Tomi. "Orphazyme stock plunges after receiving CRL from FDA after review of NPC treatment". MarketWatch. Retrieved 2021-06-30.
  8. ^ ORPHAZYME A/S (2021-06-28). "Orphazyme announces restructuring to focus resources on supporting a path forward for arimoclomol in NPC". GlobeNewswire News Room. Retrieved 2021-06-30.
  9. ^ Fox, Matthew (19 August 2020). "2 biotech stocks plummet more than 25% after the FDA rejects their drug applications". Business Insider. Retrieved 2021-06-30.
  10. ^ "FDA rejects Sesen Bio's bladder cancer pitch, sending shares spiraling back to penny stock territory". Endpoints News. Retrieved 2021-08-16.
  11. ^ Mullard, Asher (2015-07-01). "Should the FDA disclose complete response letters?". Nature Reviews Drug Discovery. 14 (7): 449. doi:10.1038/nrd4686. ISSN 1474-1784. S2CID 34872830.
  12. ^ Lurie, Peter; Chahal, Harinder S.; Sigelman, Daniel W.; Stacy, Sylvie; Sclar, Joshua; Ddamulira, Barbara (2015-06-10). "Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study". BMJ. 350: h2758. doi:10.1136/bmj.h2758. ISSN 1756-1833. PMC 4462714. PMID 26063327.
  13. ^ "SEC.gov | FCPA, Disclosure, and Internal Controls Issues Arising in the Pharmaceutical Industry". www.sec.gov. Retrieved 2021-06-30.
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