SummaryThe US Food and Drug Administration (FDA) makes its medical product marketing approval decisions based on a risk–benefit determination of safety and effectiveness.
Updated: November 12, 2018
This is often seen as a binary decision-making process in which a drug or biologic sponsor submits a package, the FDA considers it, and the agency issues either an approval or a disapproval at the end of the review process.
The reality is more complicated. The FDA engages with sponsors throughout the development process, from pre-clinical trial design to pre-submission meetings to active discussion throughout the review process. The agency often asks for additional data to supplement a submission; these requests can range from the relatively trivial, such as a clarification, to the need for an entirely new clinical trial. Even after approval, the FDA continues to work with sponsors by requesting post-market trials or monitoring.
In some cases, the FDA will issue a sponsor a Complete Response Letter (CRL) in which the agency declines to approve a drug or biologic. However, this is not a disapproval. A CRL does not necessarily indicate that a drug or biologic is not safe and effective. Rather, the FDA issues a CRL when it has reviewed the submitted data and has outstanding questions. A CRL allows the FDA to provide a sponsor with a systematic list of deficiencies detected within the submission package sent to the agency that stop short of requiring an entire resubmission. CRLs may also contain a description of inadequate data, and recommendations of actions to gain approval.1,2 Under US statute,3 a sponsor who receives a CRL has one year to re-submit the necessary supplemental information based on the recommendations in the letter.
The FDA implemented the use of CRLs in 1998 for biologics and in 2008 for drugs, to replace “approvable” and “not approvable” letters. The agency justifies this change as a move towards a “more consistent and neutral mechanism to convey that our initial review of an application is complete.”4
It is important to note that the FDA views CRLs as an “agency action”; in other words, the submission is off the agency’s plate and responsibility for next steps lies with the sponsor. This distinction is important to one of FDA’s main sources of funding. The fifth re-authorization of the Prescription Drug User Fee Act (PDUFA) requires the FDA to “review and act on”5 90% of new drug and biologics applications within 10 months. Thus, in cases where the FDA thinks it may need more data or clarification from a sponsor but the agency is coming up against its User Fee deadline, it may issue a CRL to satisfy both its action requirement and request for more information. Given that FDA has taken in over $3 billion in PDUFA V funds,6 it stands to reason that the agency takes its action requirements seriously.
CRLs are rarely made public by the product sponsors who receive them. They generally contain proprietary information and are considered trade-secret confidential regulatory correspondence by the FDA. Still, many companies choose to announce that they have received one in order to provide a development update to investors. These announcements often serve as a marker of progress and timing as PDUFA goal dates approach.
Particularly in the nascent space of biosimilar regulatory review, CRLs may indicate the FDA working with sponsors to fully understand biosimilar development while simultaneously satisfying its biosimilar user fee requirements. There are instances of currently approved biosimilars having received CRLs prior to approval, and the sponsors having announced them.7,8,9 As the FDA continues to review biosimilar applications, it is expected that the agency will continue to issue CRLs on occasion for these products prior to eventual approval if they cannot meet the current action dates of 10 months from date of submission10 (originator product reviews are due 10 months from date of FDA acceptance of the file, itself at 60 days from filing).11 In the end, the decision to continue or abandon a development program lies with the product sponsor, but the CRL will always provide guidance to aid that decision.
1. 21CFR314.110. Accessed July 21 2016. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.110
2. 21CFR601.3. Accessed July 21 2016. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=601.3
4. US FDA. “Questions and Answers Regarding the Complete Response Letter Rule.” March 2016. Accessed July 21 2016. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084143.htm
5. US FDA “PDUFA Reauthorization Performance Goals and Procedures, Fiscal Years 2013 Through 2017.” 2013. Accessed July 21 2016. Available at: http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM270412.pdf
6. US FDA. “FY 2015 PDUFA Financial Report.” Accessed July 21 2016. Available at: http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/FinancialReports/PDUFA/UCM499021.pdf
7. Bloomberg BNA. “FDA Response Delays Pfizer’s Release of Epogen Biosimilar.” October 28 2015. Accessed July 21 2016. Available at: http://www.bna.com/fda-response-delays-n57982062818/
8. US FDA. “Final Label and Labeling Review, Inflectra. Introduction.” May 19 2015. Accessed July 21 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125544Orig1s000OtherR.pdf
9. Novartis. “Novartis delivered solid Q2 despite full quarter of US Gleevec generic impact; significant positive innovation news strengthens future growth prospects. Results from important clinical trials and other highlights.” July 19 2016. Accessed July 21 2016. Available at: https://www.novartis.com/news/media-releases/novartis-delivered-solid-q2-despite-full-quarter-us-gleevec-generic-impact
10. US FDA “Biosimilar Biological Product Authorization Performance Goals and Procedures, Fiscal Years 2013 Through 2017.” 2013. Accessed July 21 2016. Available at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM281991.pdf
11. US FDA “PDUFA Reauthorization Performance Goals and Procedures, Fiscal Years 2013 Through 2017.” 2013. Accessed July 21 2016. Available at: http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM270412.pdf
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