Medicine: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.
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
- ↑ 1.0 1.1 "21 CFR 314.110". https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=314.110.
- ↑ Thayer, Ann M. (15 May 2017). "The complete response letter: The mail no one wants to receive". https://cen.acs.org/articles/95/i20/complete-response-letter-mail-one.html.
- ↑ Chandanais, Ryan (8 December 2017). "Complete Response Letters: What Drug Manufacturers Hope to Avoid". https://www.pharmacytimes.com/view/complete-response-letters-what-drug-manufacturers-hope-to-avoid.
- ↑ "FDA Complete Response Letters: The design v. reality of FDA's responses to drug applications" (in en-US). 2015-01-12. https://www.healthcarelawinsights.com/2015/01/fda-complete-response-letters-the-design-v-reality-of-fdas-responses-to-drug-applications/.
- ↑ 5.0 5.1 "MAPP 6020.5 Rev. 2: Classifying Resubmissions of original NDAs, BLAs and Efficacy Cupplements in Response to Complete Response Letters" (in en-US). https://www.fda.gov/media/72727/download.
- ↑ 6.0 6.1 "MAPPing Out The Timing Of A Complete Response Submission" (in en-US). 27 February 2015. https://camargopharma.com/resources/blog/mapping-out-the-timing-of-a-complete-response-submission/.
- ↑ Kilgore, Tomi. "Orphazyme stock plunges after receiving CRL from FDA after review of NPC treatment" (in EN-US). https://www.marketwatch.com/story/orphazyme-stock-plunges-after-receiving-crl-from-fda-after-review-of-npc-treatment-2021-06-18.
- ↑ ORPHAZYME A/S (2021-06-28). "Orphazyme announces restructuring to focus resources on supporting a path forward for arimoclomol in NPC" (in en). https://www.globenewswire.com/news-release/2021/06/28/2253542/0/en/Orphazyme-announces-restructuring-to-focus-resources-on-supporting-a-path-forward-for-arimoclomol-in-NPC.html.
- ↑ Fox, Matthew (19 August 2020). "2 biotech stocks plummet more than 25% after the FDA rejects their drug applications" (in en). https://www.businessinsider.com/biomarin-galapagos-gilead-stock-price-fda-issues-crl-drug-rejection-2020-8.
- ↑ "FDA rejects Sesen Bio's bladder cancer pitch, sending shares spiraling back to penny stock territory" (in en). https://endpts.com/fda-rejects-sesen-bios-bladder-cancer-pitch-sending-shares-spiraling-back-to-penny-stock-territory/.
- ↑ Mullard, Asher (2015-07-01). "Should the FDA disclose complete response letters?" (in en). Nature Reviews Drug Discovery 14 (7): 449. doi:10.1038/nrd4686. ISSN 1474-1784.
- ↑ 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" (in en). BMJ 350: h2758. doi:10.1136/bmj.h2758. ISSN 1756-1833. PMID 26063327. PMC 4462714. https://www.bmj.com/content/350/bmj.h2758.
- ↑ "SEC.gov | FCPA, Disclosure, and Internal Controls Issues Arising in the Pharmaceutical Industry". https://www.sec.gov/news/speech/2015-spch030315ajc.html#.VPcThIe2H-o.
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