Utilize the New FDA Marketing Application Filing Checklist to Prevent RTFs

Imagine this – you're working at a small biotechnology company and you just filed your first New Drug Application (NDA). Let’s assume you don’t have orphan designation, but you have clinical data and need to pay the ~$4.7 million PDUFA fee for the FDA to review your NDA.  

To get here, you’ve already spent years collecting data (CMC, nonclinical, clinical) and engaged in multiple FDA interactions (Regulatory) to showcase the history of your product and take the FDA along your journey through various stage gates. Hopefully, you’re on the path to approval with all your diligent NDA-readiness efforts. Likely, within 60 days, you’ll receive an NDA filed letter instead of a refuse to file (RTF) notification.  

Let’s discuss the key concerns with an RTF and how the new FDA release of filing checklists is intended to help reduce this occurrence and assuage concerns. 

Support and Momentum from the FDA 

On October 23, 2025, FDA released filing checklists for marketing applications (i.e., an NDA) in their latest update of CDER’s MAPP 6025.4 Good Review Practices: Refuse to File. After an NDA or Biologics License Application (BLA) is filed, the FDA has up to 60 days to determine if the marketing application submitted by a sponsor will be acceptable by granting an NDA/BLA filed letter and is ready for technical review, or if they need to issue a refuse to file (RTF) letter noting minor or significant deficiencies. If an RTF is issued by the FDA, it could take time to remediate, delaying innovative treatment to patients. To prevent this, FDA released example checklists to help aid drug developers and de-risk an RTF.  

Originally, both the CDER manual of policies and procedures was effective on Oct 11, 2013, and accompanied later by the draft guidance for industry from Dec 2017, titled Refuse to File: NDA and BLA submissions to CDER were the two main documents used to help drug developers prevent potential RTFs. 

When the FDA reviews a marketing application, they are searching for easily correctable deficiencies or complex significant deficiencies. The easily correctable deficiencies can be classified into examples such as navigation problems, incomplete or missing forms, missing right to reference, financial disclosure statements, incorrectly worded debarment certification statement, and labeling in structure product label format. The complex significant deficiencies may include the following, but is not limited to: 

• Lacking or inadequately organized material 

• Parts of application containing inadequate information for one or more indications when multiple indications are submitted in the same application 

• An application relying on a single adequate and well-controlled trial for demonstration of effectiveness if prior communication between the FDA and applicant determined the need for more than one trial 

• Failure to submit an assessment of studies related to the potential abuse of a drug 

• Required content is not submitted electronically where the FDA has specified the format of such submissions 

• For new molecular entity NDAs or original BLAs, if the minor components agreed upon for late submission at the pre-submission meeting are not received within 30 calendar days after receipt of the application 

Both the MAPP and RTF guidance have been around for over or nearly a decade, and regulatory professionals have used these materials to guide sponsor companies to prevent filing issues. With the addition of this new checklist, it adds one more layer for sponsors to consider before filing their marketing application to ensure a smoother review process as well as future time and cost savings. 

Real-World Experience 

At Halloran, we have worked on several marketing applications, and we keep these considerations in mind as we conduct a BLA/NDA gap assessment, build an BLA/NDA content tracker with list of documents and timelines, or ensure that the organization, formatting, or navigation of documents are easy for the FDA reviewer. We understand we are helping sponsors tell the product’s story – the help and hope they provide to their patients.  

As a result, we are excited about these filing checklists that were just released by the FDA because we are often asked by clients ‘why doesn’t the FDA provide guidance with the full BLA/NDA checklist on what would be essential?’ Usually, sponsors hire regulatory professionals (as internal team members, advisors, or consultants) with marketing application experience to help them navigate the prevention of a filing review issue with the RTF.  

Insights and Recommendations for Product Development Sponsors 

In reviewing these FDA checklists in Appendix C, which spans about 30 pages of the manual of policies and procedures, it is organized by discipline, making it easy to navigate: 1) Clinical, 2) Nonclinical, 3) Biostatistics, 4) Clinical Pharmacology, 5) Product Quality/CMC. Furthermore, I find it helpful because it contains even more detail that would help expand upon an NDA-readiness gap analysis. Upon review of a majority of the questions, it is consistent with the components we look for to better inform our clients and de-risk their programs.  

Here are some key inclusions in the list of questions for sponsor companies to consider: 

General 

• Comply with electronic common technical document (eCTD) 

• Legibility, organization, navigation, indexed, pagination, bookmarks 

• Documents provided in English or English translations 

• Module 2 summaries across nonclinical, clinical, and CMC 

• Information requested by the FDA during pre-submission discussions 

• Potential Advisory Committee considerations 

Clinical 

• Benefit-risk analysis for the product 

• Integrated summaries of safety and efficacy 

• Requisite number of adequate and well-controlled studies in the application 

• Pivotal efficacy studies appear to be adequate and well-controlled, and endpoints conform to previous Agency commitments/agreements 

• The requisite number of patients exposed for safety   

• Narrative summaries of serious adverse events 

• Pediatric assessments or documentation for waiver and/or deferrals 

• Labeling considerations for Pregnancy and Lactation Labeling Rule (PLLR) 

• Case Report Forms 

• Good Clinical Practice statements 

Nonclinical 

• Full completed reports of all nonclinical studies or risk assessments (i.e., pharmacology, ADME, toxicology) 

• Route of administration used in animal studies appear to be the same as the intended human exposure route 

• Statement identifying the established pharmacologic lass 

• Required SEND datasets for the appropriate nonclinical studies (requirements based upon study initiation date and study type) 

• Good Laboratory Practice statements 

Biostatistics 

• Summary of efficacy/safety clinical trials in tabular format with study ID, design, sample size, endpoint analysis, preliminary findings 

• Assessment of protocols and study reports such as statistical analysis plans, interim analyses, and novel statistical methodology 

• Electronic data assessment: Analysis datasets, dataset structure (SDTM or ADaM), define files, safety data organization, site(s) that could lead to inspection (BIMO), and format is compliant (i.e., CDISC) 

Clinical Pharmacology 

• Clinical Pharmacology Package: In vitro studies, in vivo studies, biopharmaceutics, human pharmacokinetics, intrinsic factors (i.e., race, sex, geriatrics, pediatrics, hepatic/renal impairment), extrinsic factors (effect on/of primary drug), pharmacodynamics, pharmacokinetics/pharmacodynamics (PK, PD, QT), and pharmacometrics (PopPK, Exposure-Efficacy/Safety) 

• Bioequivalence, bioavailability, and data  

• Metabolism and drug-drug interaction 

• Rationale for dose/dosing interval and dose adjustment 

• Analysis datasets, source code, input files, and key analysis output in addition to study reports 

Product Quality/CMC 

• Environmental assessment report 

• Drug Master Files, as applicable 

• Facility Information: Drug substance and drug product manufacturing sites, packaging, control testing, laboratory sites 

• Drug Substance (DS): Manufacturer information, characterization, control of DS, reference standards or materials, container closure system, and stability 

• Drug Product (DP): Description and composition, pharmaceutical development, manufacture information, manufacturing process, control of excipients, control of DP, container closure system, and stability 

• Biopharmaceutics: In vitro dissolution/release specification of DP, bridging of different formulations, biowaiver requests, BCS designation, and executed batch records for DS and DP 

In summary, there is a wealth of detail provided by the FDA, but it is understood that these lists are not fully comprehensive. Also, this checklist does not guarantee a sponsor an automatic approval; rather, it provides another added step to help prevent RTFs for marketing applications. This shows the collaborative nature of the FDA with sponsor companies to ensure patients who need these innovative therapies can get access to them faster.  

Halloran Consulting Group, a ProductLife Group company, prepares many biotech organizations with successful marketing application readiness and submissions. If you need support, we look forward to the conversation. Contact us today. 

References 

1. Food and Drug Administration. FDA News Release: FDA Publishes Filing Checklists to Prevent Submission Delay; October 23, 2025. Accessed on January 12, 2026. https://www.fda.gov/news-events/press-announcements/fda-publishes-filing-checklists-prevent-submission-delays  

1. Food and Drug Administration. Center for Drug Evaluation and Research, Manual of Policies and Procedures (MAPP 6025.4, Rev 1), Office of New Drugs, Good Review Practice: Refuse to File; October 23, 2025. Accessed on January 12, 2026. https://www.fda.gov/media/87035/download  

1. Food and Drug Administration. Draft Guidance for Industry: Refuse to File: NDA and BLA Submissions to CDER; December 2017. Accessed on January 12, 2026. https://www.fda.gov/media/109758/download   

1. Food and Drug Administration. Prescription Drug User Fee Amendments; Content Current as of November 14, 2025. Accessed on January 12, 2026. https://www.fda.gov/industry/fda-user-fee-programs/prescription-drug-user-fee-amendments