When a new drug application or biologics license application is deemed incomplete by the FDA, the agency can decide not to review the application. So when can this occur? On Tuesday, the agency released draft guidance on what incompleteness means and when it can lead to a “refusal to file” decision.
Explained simply: Refuse-to-file actions allow the FDA to inform a sponsor as quickly as possible of deficiencies in an NDA or BLA, helping companies to correct such issues rather than wait for FDA to issue a complete response letter.
Incomplete applications, including applications for which minor components have not been received within 30 calendar days after receipt of the original application, as may have been agreed upon at a pre-submission meeting, may also be refused for filing, the agency explains.
Since the early 1990s, the FDA’s processes and timelines for reviewing NDAs and BLAs have evolved, thanks at least in part to the Prescription Drug User Fee Act. And with this evolution, the complexity of applications and how FDA determines completeness have become more challenging, the agency explains.
On 19 May 2017, FDA withdrew its previously published guidance from 1993 on refuse to file actions.
FDA says it is issuing this guidance to update and clarify the Center for Drug Evaluation and Research’s procedures for determining whether an application should be refused for filing because it is incomplete. This draft also includes procedures for certain BLAs and supplemental BLAs as CDER is responsible for certain biological products subject to licensing under the Public Health Service Act, though the draft does contain information on abbreviated new drug applications for generic drugs. Previous guidance on what may cause FDA to refuse to receive ANDAs was released in December 2016.
Filing issues generally are grouped into two categories, the draft explains: Deficiencies that can be corrected before filing and are not discussed in the draft, and complex significant deficiencies that cannot be corrected before filing and may result in a refusal to file.
Examples of such deficiencies that fall into the later bucket can include:
(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.”
Other specific examples of refuse to file scenarios, FDA says, also can be found in MAPP 6025.4 Good Review Practice: Refuse to File available on the Manual of Policies and Procedures.
Filed Over Protest
The draft guidance further notes scenarios when, within 30 days of the date of the review division’s refuse to file notification, the applicant requests in writing an informal conference with FDA to discuss whether the agency should file the application.
If after the informal conference, the applicant requests that 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 and the filing date will be designated as 60 days after the receipt date of the informal conference meeting request.
But the draft adds: “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.
First published here. Regulatory Focus is the flagship online publication of the Regulatory Affairs Professionals Society (RAPS), the largest global organization of and for those involved with the regulation of healthcare and related products, including medical devices, pharmaceuticals, biologics and nutritional products. Email firstname.lastname@example.org for more information.
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