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.{{Cite web|title=21 CFR 314.110|url=https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=314.110|archive-url=https://web.archive.org/web/20021128085745/http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=314.110|url-status=dead|archive-date=November 28, 2002|access-date=2021-06-30|website=www.accessdata.fda.gov}} 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, Abbreviated New Drug Application or Biologics License Application. The FDA may either approve the application or issue a Complete Response Letter.{{Cite web|last=Thayer|first=Ann M.|date=15 May 2017|title=The complete response letter: The mail no one wants to receive|url=https://cen.acs.org/articles/95/i20/complete-response-letter-mail-one.html|access-date=2021-06-30|website=ACS C&EN}} Grounds behind issuing a CRL may include labeling issues, current Good Manufacturing Practice concerns or concerns about the safety or effectiveness of the drug.{{Cite web|last=Chandanais|first=Ryan|date=8 December 2017|title=Complete Response Letters: What Drug Manufacturers Hope to Avoid|url=https://www.pharmacytimes.com/view/complete-response-letters-what-drug-manufacturers-hope-to-avoid|access-date=2021-06-30|website=Pharmacy Times}}
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.{{Cite web|date=2015-01-12|title=FDA Complete Response Letters: The design v. reality of FDA's responses to drug applications|url=https://www.healthcarelawinsights.com/2015/01/fda-complete-response-letters-the-design-v-reality-of-fdas-responses-to-drug-applications/|access-date=2021-06-30|website=Healthcare Law Insights|language=en-US}}
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.{{Cite web |title=MAPP 6020.5 Rev. 2: Classifying Resubmissions of original NDAs, BLAs and Efficacy Cupplements in Response to Complete Response Letters |website=Food and Drug Administration, Center for Drug Evaluation and Research |language=en-US |access-date=2021-06-30 |url=https://www.fda.gov/media/72727/download}} Where a sponsor decides to submit a response to a CRL, the response is classified within 30 days, if the response is complete.{{Cite web|date=27 February 2015|title=MAPPing Out The Timing Of A Complete Response Submission|url=https://camargopharma.com/resources/blog/mapping-out-the-timing-of-a-complete-response-submission/|access-date=2021-06-30|website=Camargo|language=en-US}} 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. 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 Niemann–Pick disease, type C,{{Cite web|last=Kilgore|first=Tomi|title=Orphazyme stock plunges after receiving CRL from FDA after review of NPC treatment|url=https://www.marketwatch.com/story/orphazyme-stock-plunges-after-receiving-crl-from-fda-after-review-of-npc-treatment-2021-06-18|access-date=2021-06-30|website=MarketWatch|language=EN-US}} forcing the company to restructure.{{Cite web|last=ORPHAZYME A/S|date=2021-06-28|title=Orphazyme announces restructuring to focus resources on supporting a path forward for arimoclomol in NPC|url=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|access-date=2021-06-30|website=GlobeNewswire News Room|language=en}} BioMarin Pharmaceutical lost over 30% of its value when a CRL was issued in respect of its hemophilia A gene therapy, valoctocogene roxaparvovec.{{Cite web|last=Fox|first=Matthew|date=19 August 2020|title=2 biotech stocks plummet more than 25% after the FDA rejects their drug applications|url=https://www.businessinsider.com/biomarin-galapagos-gilead-stock-price-fda-issues-crl-drug-rejection-2020-8|access-date=2021-06-30|website=Business Insider|language=en}} Sesen Bio's stock price dropped over 80% after reporting a CRL for Vicineum as a treatment for a type of bladder cancer.{{Cite web|title=FDA rejects Sesen Bio's bladder cancer pitch, sending shares spiraling back to penny stock territory|url=https://endpts.com/fda-rejects-sesen-bios-bladder-cancer-pitch-sending-shares-spiraling-back-to-penny-stock-territory/|access-date=2021-08-16|website=Endpoints News|language=en}}
Disclosure
Typically, CRLs are not disclosed publicly as they often include proprietary information.{{Cite journal|last=Mullard|first=Asher|date=2015-07-01|title=Should the FDA disclose complete response letters?|journal=Nature Reviews Drug Discovery|language=en|volume=14|issue=7|pages=449|doi=10.1038/nrd4686|s2cid=34872830 |issn=1474-1784|doi-access=free}} Press releases, when issued, typically do not include most of the details contained in the CRL, including the reasons behind it.{{Cite journal|last1=Lurie|first1=Peter|last2=Chahal|first2=Harinder S.|last3=Sigelman|first3=Daniel W.|last4=Stacy|first4=Sylvie|last5=Sclar|first5=Joshua|last6=Ddamulira|first6=Barbara|date=2015-06-10|title=Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study|url=https://www.bmj.com/content/350/bmj.h2758|journal=BMJ|language=en|volume=350|pages=h2758|doi=10.1136/bmj.h2758|issn=1756-1833|pmid=26063327|pmc=4462714}} 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.{{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}}