backThe Food and Drug Administration (FDA) has issued a Refuse-to-File (RTF) letter to Moderna, Inc. regarding its Biologics License Application (BLA) for the investigational mRNA-based influenza vaccine “mRNA-1010.” Moderna announced FDA’s action in a February 10, 2026 press release 1See “Moderna Receives Refusal-to-File Letter from the U.S. Food and Drug Administration for Its Investigational Seasonal Influenza Vaccine, mRNA-1010.” February 10, 2026. https://feeds.issuerdirect.com/news-release.html?newsid=7346090610333866&symbol=MRNA and disclosed the RTF letter. 2See FDA REFUSAL TO FILE communication. February 3, 2026. https://static.modernatx.com/pm/6cef78f8-8dad-4fc9-83d5-d2fbb7cff867/38ab7558-636c-40d1-b49a-c8f51a7afa1a/38ab7558-636c-40d1-b49a-c8f51a7afa1a_viewable_rendition v.pdf Based on publicly available information, this FDA decision was unexpected and may signal new challenges and roadblocks in the agency’s review of novel drugs and biologics as well as unexpected involvement by FDA leadership. Separately, this development highlights the lack of transparency regarding FDA’s use of the RTF regulatory mechanism to delay review of marketing applications.
The RTF letter states that the decision is based on a single issue: the lack of data from an “adequate and well-controlled clinical trial” consistent with FDA advice regarding comparison of “mRNA-1010” versus an approved influenza vaccine recommended for use in older adults. In its press release, however, Moderna argues that the company provided the analyses requested by the Center for Biologics Evaluation and Research (CBER). Separately, the RTF decision is noteworthy because of the infrequency of its use as a regulatory tool to delay FDA review. In addition, the RTF letter was signed by Vinay Prasad M.D., Director of CBER. This is notable because RTF letters are customarily signed by the Office Director of the relevant review office, not the Center Director. 3See CBER SOPP 8404: Refusal to File Procedures Version:12. Effective Date: December 15, 2025. https://www.fda.gov/media/111632/download
Here we discuss the RTF regulatory framework, its use and limitations, and issues specific to the RTF letter regarding the “mRNA-1010” vaccine.
1. THE REFUSE-TO-FILE FDA REGULATORY FRAMEWORK. RTF is a formal regulatory mechanism that allows FDA to decline to review original applications and certain New Drug Application (NDA) or BLA supplements (collectively, applications) that the agency deems to have critical insufficiencies that do not permit a substantive review. 4Under 21 C.F.R. § 601.2(a), “an application for a biologics license application shall not be considered as filed until all pertinent data and information have been received by the Food and Drug Administration.” RTF determinations by CBER are based on submissions that fail to contain information required under the Public Health Service Act; the Federal Food, Drug, and Cosmetic Act; or applicable regulations. Within 60 days after an initial submission, FDA conducts a filing review to determine if the application is sufficiently complete to permit substantive and meaningful review. Applicants with submissions that FDA determines are incomplete are issued RTF letters. In response, the applicant can modify the application and resubmit it. Alternatively, the applicant can “file over protest” and request FDA to conduct a full review of the original submission.
As outlined in CBER Standard Operating Policy and Procedure (SOPP) 8404 5 See CBER SOPP 8404: Refusal to File Procedures Version:12. Effective Date: December 15, 2025. https://www.fda.gov/media/111632/download , RTF decisions can be made by CBER based on any of the following findings:
- Administrative incompleteness. For example, the submission omits information required for FDA administrative review.
- Scientific omissions. Such omissions include lack of critical data including but not limited to failure to include analyses needed to evaluate safety, purity and potency; adequate directions for use including clinical information; quality, manufacturing and facility information; pharmacology/toxicology data; and/or critical protocol-specified statistical analyses.
- Inadequate content, presentation, or organization of information that prevents substantive and meaningful review. Examples of deficiencies include illegibility; lack of translation of any portion into English; uninterpretable tables, graphs or figures; failure to reference location of data and records in summary reports; and absence of complete protocols for clinical investigations.
2. TRENDS IN REFUSE-TO-FILE ACTIONS BY FDA. FDA does not publicly disclose RTF letters from CBER or the Center for Drug Evaluation and Research (CDER) at the time of issuance to the applicant. Instead, RTF letters are only publicly disclosed if the application is approved; in such cases, the RTF letter may be included in the product’s approval information packet on the FDA website. The most complete public report regarding trends in FDA issuance of RTF letters is a 2021 analysis authored by senior CDER officials. Among the 2,475 NDA applications submitted during the period of January 1, 2008 to December 31, 2017, only 98 (4%) received RTF letters. 6 See Chalal HS, Mukerjee S, Sigelman DW, Temple R. “Contents of US Food and Drug Administration Refuse-to-file Letters for New Drug Applications and Efficacy Supplements”. JAMA Internal Medicine. 2021; 181(4):522-529
- Successful resubmissions. Among the 98 applications that received RTF letters, 53 (54%) were resubmitted and successfully addressed the deficiencies.
- Timelines for FDA actions. However, the report disclosed that receipt and response to an RTF letter creates a substantial regulatory review delay. Of the 53 successful resubmissions, the median time for resubmission in response to an RTF letter was 182 days. The median time from original submission to approval following an RTF letter was 784 days.
- FDA reasons for issuance of RTF letters. The report analyzed seven domains of stated reasons for RTF letters: chemistry, manufacturing and controls; general scientific and technical; clinical safety; application organization and legal compliance; clinical efficacy; clinical pharmacology and biopharmaceutics; and nonclinical. The report clarified that only 2% of applications had deficiencies in all domains. Overall, clinical efficacy deficiencies were identified in 44.7%, safety deficiencies in 36.9% and both in 26.2% of RTF letters. In addition, deficiencies in chemistry, manufacturing and controls were present in 19.4% of RTF letters.
- Public disclosure of RTF letters by applicants. Notably, the FDA analysis identified that applicants publicly disclosed the existence of only 15.5% of the RTF letters in press releases or U.S. Securities and Exchange Commission filings.
- Sponsor’s adherence to FDA pre-submission advice. FDA emphasized that in 26% of the RTF letters, the applicant ignored explicit pre-submission advice provided by FDA.
In October 2025, FDA stated that over the prior 10 years, more than 200 applications to CDER have resulted in an RTF notification. (It is unclear whether this statistic includes both NDAs and abbreviated new drug applications.) FDA stated that applications involving a new molecular entity that received an RTF experienced an average delay of 426 days before the application was resubmitted. 7See FDA, News Release, FDA Publishes Filing Checklists to Prevent Submission Delays (updated Oct 23, 2025), https://www.fda.gov/news-events/press-announcements/fda-publishes-filing-checklists-prevent-submission-delays
3. THE RTF LETTER REGARDING “mRNA-1010” VACCINE. The FDA letter issued on February 3, 2026, which was publicly disclosed by Moderna, lists only one reason for the RTF: “CBER does not consider the application to contain a trial ‘adequate and well-controlled’ and the application is therefore, on its face, inadequate for review. This is because your control arm does not reflect the best-available standard of care in the United States at the time of the study. I note that this determination is consistent with FDA’s advice given to you prior to your study.” FDA advises that if the company disagrees with the RTF decision, Moderna should request a Type A meeting within 30 days of its receipt of the RTF letter. FDA also notes that if, after the meeting, Moderna still does not agree with FDA’s decision, it can request that the application be filed over protest. In its February 10th press release, Moderna disclosed that it has requested a Type A meeting.
Takeaways
Traditionally, RTF determinations have focused on whether an application is “complete” in the sense of whether the application contains the minimum required information for FDA to conduct a substantive review. This stage of the submission process has not, historically, been a point at which FDA judges the substantive adequacy of the scientific data presented—as indicated, for instance, by the relatively small percentage of NDA submissions that received an RTF decision between 2008-2017. It is too soon to tell whether FDA’s extraordinary RTF decision for Moderna’s vaccine represents a unique situation or heralds a broader shift in how CBER intends to interpret the applicable regulation and SOPP. The possibility of an RTF action provides an important reminder that sponsors must thoughtfully anticipate FDA scrutiny, perhaps especially on cutting edge topics where FDA leadership has expressed skepticism.
In addition to review/approval delays and the administrative burdens noted above, there may be other important consequences for sponsors. For example, following an RTF action, FDA must by law refund 75% of the application fee that was paid when the application was submitted. The subsequent filing of a refused application (including an application over protest) is considered a new application for user fee purposes—necessitating the payment of an additional $1.2 million fee. In addition, priority review may be converted to standard review and other NDA/BLA review clock commitments may not apply. Depending on the facts associated with a specific application, securities derivative suits are always a risk if filing realities do not match prior predictions.
King & Spalding is actively advising clients that are facing FDA’s invocation of NDA/BLA procedural mechanisms to limit specific approvals. If you have questions regarding this client alert or would like assistance considering the implications of the Moderna RTF decision or other administrative tools, we are glad to help. Please contact Beverly Lorell, Gary Messplay, Chris Markus, Kyle Sampson, or Lauren Roth for more information.