Preventing FDA Refuse-to-File Decisions for NDAs, ANDAs, and BLAs: A Quick Guide

Earlier this month, FDA released a new draft guidance offering details on what constitutes an "incomplete" new drug application (NDA) or biologics license application (BLA), and when these issues can lead to a "refuse to file" decision.

As a brief primer, FDA's refuse-to-file action quickly informs sponsors of a problem in an NDA or BLA so they can correct issues and avoid waiting for a complete response letter from the agency.

An incomplete application subject to refusal can also be one for which minor components have not been received within 30 calendar days after receipt of the original application.

The Context for Change

The agency has continuously developed its process for reviewing NDAs and BLAs since the 1990s following the Prescription Drug Use Fee Act. However, as FDA admits, this evolution has undoubtedly made these processes far more complex and difficult. Recognizing a need to simplify, FDA withdrew its 1993 guidance which established refuse to file actions.

Regulators say this new guidance is intended to update and clarify the CDER's procedures for determining whether an NDA or BLA application should be refused for filing due to incompleteness. The draft also explains procedures for specific BLAs and supplemental BLAs given CDER's responsibility for some biological products licensed under the Public Health Service Act.

While this draft does not offer information on abbreviated new drug applications (ANDAs) for generic drugs, we've summarized the key points from a previous guidance released last year.

Categories of Filing Issues

The new draft groups filing issues into two categories:

1. Deficiencies that can be corrected before filing and are not discussed in the draft, and;

2. Complex significant deficiencies that cannot be corrected before filing and may result in a refusal to file.

While the first category is more or less self-explanatory, we've offered some of examples given for the second category below.

Examples of "complex significant deficiencies that cannot be corrected before filing and may result in a refusal to file" for NDAs and BLAs

"(a) Materially lacking or inadequately organized applications that would not permit timely, efficient, and complete review by all relevant review division disciplines as outlined in the guidance for review staff and industry Good Review Management Principles and Practices for PDUFA Products.

(b) Parts of applications that contain inadequate information for one or more indications when multiple indications are submitted in the same application. The FDA may accept for filing those parts of an application that represent complete submissions for particular indications but refuse to file those parts that are determined to be incomplete for other indications.

(c) An application that relies on a single adequate and well-controlled trial for a demonstration of effectiveness if prior communication between the FDA and the applicant (i.e., end-of-phase 2 meeting) determined the need for more than one trial to demonstrate effectiveness and if the submitted justification for reliance on a single trial is inadequate. (The FDA may determine that data from a single adequate and well-controlled trial and confirmatory evidence is sufficient to establish effectiveness (see section 505(d) of the FD&C Act); this is further discussed in the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.)

(d) Failure to submit an assessment of studies related to the potential abuse of a drug, necessary to inform drug scheduling under the Controlled Substances Act and the development of drug product labeling. This requirement applies when the drug affects the central nervous system (as determined in animal or human studies), is chemically or pharmacologically similar to other drugs with known abuse potential (such as an opioid, stimulant, depressant, or hallucinogen), or produces psychoactive effects such as euphoria, mood changes, depression, or hallucinations. See § 314.50(d)(5)(vii) and the guidance for industry Assessment of Abuse Potential of Drugs.

(e) Required content is not submitted electronically where the FDA has specified the format of such submissions in guidance pursuant to section 745A of the FD&C Act or required content is not submitted in an electronic format that the FDA can review, process, and archive, where such electronic submissions are required by an applicable regulation. Electronic submission issues that CDER considers to be filing issues include particular organization, file format, coding, or formatting problems that are specified in applicable guidances issued pursuant to section 745A(a) of the FD&C Act.

(f) NME [new molecular entity] NDAs or original BLAs reviewed under the Program, if the minor components agreed upon for late submission at the presubmission meeting are not received within 30 calendar days after receipt of the application."

FDA refers readers to MAPP 6025.4 Good Review Practice: Refuse to File available on the Manual of Policies and Procedures for more examples of refuse-to-file scenarios.

Filing Applications Over Protest

The draft guidance also lays out possible scenarios when applicants request (within 30 days of the review division's refusal to file notification) an informal conference with FDA (in writing) to discuss filing of the application.

If after this conference, an applicant requests the review division file the application with or without amendments to correct the deficiencies, the review division will file the application over protest, notify the applicant in writing, and review it as filed. The filing date will be designated as 60 days after the receipt date of the informal conference meeting request.

However, the draft includes important specific stipulations:

"Applications for NME NDAs or original BLAs received between October 1, 2012, through September 30, 2017, that are filed over protest will not be reviewed under the Program. Alternatively, the applicant may amend the NDA and resubmit it, and the review division will make a separate determination whether the resubmitted NDA may be filed." The draft also includes an appendix on select refuse-to-file authorities."

Revised Refuse-to-Receive ANDA Guidelines

In December of 2016, FDA released a guidance offering recurrent deficiencies that have led the agency to refuse-to-receive ANDA submissions that were "not substantially complete.” It also describes how FDA will assess deficiencies identified during its filing review to determine whether an ANDA should be received.

Minor Corrections in Seven Calendar Days

As part of the Generic Drug User Fee Act (GDUFAII) reauthorization plan, FDA says it will provide ANDA applicants an opportunity to correct minor deficiencies or amend an ANDA within seven calendar days. If the requested information is not received within this time, FDA says it will refuse to receive the ANDA.

Ten or More Minor Deficiencies or One or More Major Deficiency

If ten or more minor deficiencies or one or more major deficiency exist within an ANDA, FDA will not consider it to be substantially complete.

A Quick Look at the Numbers

It's important to note that the number of ANDA submissions that have received a refuse-to-receive decision have been comparatively low over the last several years, especially compared to the 1,725 complete response letters issued for ANDAs in 2016 alone.

Between Fiscal Years 2013 and 2015, FDA refused to receive 379 ANDAs for reasons other than a failure to pay a GDUFA fee. Of all original ANDA submissions, FDA refused to receive 14% of ANDAs in FY 2013, 10% in FY 2014 and 14% in FY 2015.

Need expert help planning, crafting, and submitting an NDA, ANDA, or BLA to the FDA? Our large staff of industry specialists and former FDA personnel can help.

Learn more about our Regulatory Affairs services below ⤵