Imagine dedicating years and millions of dollars to developing a life-changing new medicine, only to have its application refused by the FDA due to a preventable administrative error. This costly setback, the Refuse to File (RTF) action, consumes immense resources and delays promising treatments from reaching patients. The FDA RTF checklists used by its own reviewers can mitigate that.
When a New Drug Application (NDA) or Biologics License Application (BLA) is submitted, CDER staff conduct an initial filing review to assess if the application is “substantially complete” and reviewable. This step is critical because incomplete applications can lead to multiple review cycles and inefficient use of CDER resources.
If the application contains only small, easily correctable deficiencies—like electronic navigational problems or a missing right of reference—the sponsor may be given a quick opportunity to remedy them. However, if the deficiencies are more complex and significant, the FDA will issue a formal Refuse to File (RTF) notification, generally forcing sponsors to resubmit a complete application. An RTF is a time-consuming event for all parties and a major threat to a product’s timeline. Over the last decade, more than 200 applications to CDER have resulted in an RTF. Applications for a new molecular entity (NME) that receive an RTF experience a staggering average delay of 426 days before resubmittal, highlighting the high cost of preventable procedural oversights.
The RTF checklists are available on the FDA’s website to help sponsors self-check their applications before submission of their market approval application. Most sponsors even include pre-filled RTF checklists with their applications to assist the FDA reviewers. The RTF checklists reflect the FDA’s core expectation that applications be complete at the time of submission, rejecting a “piecemeal approach” to building an application through later amendments. The guidelines for NDAs and BLAs are contained within CDER’s Manual of Policies and Procedures (MAPP) 6025.4, Good Review Practice: Refuse to File. This document identifies the types of complex and significant deficiencies that support an RTF, such as missing required sections of an application, inadequate facility descriptions, or the absence of critical clinical investigations needed to evaluate effectiveness and safety.
For generic drugs, the filing review of Abbreviated New Drug Applications (ANDAs) is detailed in MAPP 5200.14. This document details the specific items an Office of Generic Drugs (OGD) reviewer will check across the Common Technical Document (CTD) format. For instance, a reviewer will verify the submission of:
- An appropriate patent certification or statement for every patent listed in the Orange Book for the reference listed drug (RLD).
- Complete bioequivalence summary tables, including pilot and pivotal data, submitted in both PDF and Word files.
- Detailed quality information, such as the unit composition, justification for all inactive ingredients, and stability data for the finished dosage form.
These detailed checklists empower sponsors to perform a self-audit before submission, mitigating the risk of rejection. Although the checklists are not necessarily comprehensive, as the agency alone ultimately determines fileability, they represent an invaluable tool for sponsors to meet the minimum threshold of a reviewable application. For drug sponsors, these checklists are not just a guide but a powerful tool to ensure transparent, accurate, and complete communication moving forward, increasing efficiency and eliminating preventable RTF actions.
