Regulatory Focus™ > News Articles > New FDA Manual Clarifies Refuse-to-File Criteria for Drug Submissions

New FDA Manual Clarifies Refuse-to-File Criteria for Drug Submissions

Posted 17 October 2013 | By Alexander Gaffney, RAC

When is a marketing application not even worth looking at? For the US Food and Drug Administration (FDA), it's a question with very real implications, both for drugs and medical devices being considered under its user fee programs. If FDA accepts an application that is not approvable without a significant amount of work, it risks wasting resources, delaying eventual approval of a product by interrupting development and hurting FDA's average review times under its user fee programs.


It's been a serious enough problem on the device side, where regulators have for years complained about gaps in the quality of applications, that FDA has issued draft guidance on the topic in the form of Refuse to Accept (RTA) Policy for 510(k)sand Acceptance and Filing Reviews for premarket Approval Applications (PMAs).

At their core, the guidance documents have been intended to clarify the criteria by which FDA will determine if an application has the basic component parts needed to support a regulatory review. It is not, as regulators concede, intended to assess whether the data collected in support of the application supports the indication, but rather to assess whether the data is there at all.

The latter distinction has been a contentious one for device companies, which said in October 2012 that they were worried FDA's criteria were venturing outside of administrative review parameters (e.g. the presence or non-presence of material) and into subjective and substantive review (e.g. if the data could ever support the sought-after indication).

Refuse-to-File: Drugs

But as a new Manual of Policies and Procedures (MAPP) document released by FDA illustrates, devices aren't the only products FDA utilizes a refuse-to-file system for. Good Review Practice: Refuse to File, a MAPP published on 10 October 2013 by the Center for Drug Evaluation and Research's (CDER) Office of New Drugs (OND), seeks to lay out similar filing requirements on the pharmaceutical side of the agency.

The MAPP specifically focuses on 21 CFR 314.101(d)(3), which states that FDA "may refuse to file an application or may not consider an abbreviated new drug application to be received" if an application "does not on its face contain information required under section 505(b), section 505(j), or section 507 of the [Federal Food Drug and Cosmetic Act] and 314.50 or 314.94 [of the Code of Federal Regulations]."

As FDA notes, 314.101(d)(3) is significantly less clear than other parts of 314.101(d), requiring additional guidance to be given to FDA staff on how to interpret its provisions.

Adequacy of Information

FDA explains in its MAPP that it is important to consider not just the presence of information, but also "its adequacy," the assessment of which can potentially lead to "substantial concerns that may affect conclusions drawn from submitted information and ultimately affect approval of the application."

It is, in other words, a review format that is conceptually similar to the one that raised concerns among medical device manufacturers, who feared that the assessments constituted a miniature review in and of themselves.

The MAPP, though, clarifies that refuse-to-file actions should be based only on filing issues, and not review issues. That being said, "many issues do not fit easily into these categories and often whether an issue is a filing or review issue depends on the magnitude of the deficiency," FDA hedged.

For example, a deficiency is not involved with assessments or risk or benefit, nuances of protocol design, adequacy of statistical plans or study endpoints/trial design, or the acceptability of a surrogate endpoint.

Refuse to File Criteria

But for FDA, the ability to separate the wheat from the chaff is necessary to preserve adequate review resources for applications that stand a chance of approval. Wasting time on an application with no chance for approval takes time away from one that does.

FDA said its new policy will be to refuse to file any applications that:

  • are materially incomplete
  • are disorganized to the extent that they could not be efficiently reviewed
  • have parts that "contain inadequate information for one or more indications" when more than one indication is submitted at once
  • contain an inadequate number of trials to support approval, if a number was established in a prior meeting with FDA

The responsibility to meet agreed-upon criteria is important, FDA said. "Applications are expected to be complete as agreed upon by the FDA and the applicant at the pre-submission meeting," FDA explained. "Incomplete applications, including applications with minor components not received within 30 calendar days after receipt of the original application, as agreed at the pre-submission meeting, will be subject to a refuse-to-file (RTF) decision."

MAPP: Good Review Practice: Refuse to File

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