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Life Science News - "Refuse to File: NDA and BLA Submissions to CDER Guidance for Industry"

Excerpt from U.S. Department of Health and Human Services' Guidance "Refuse to File: NDA and BLA Submissions to CDER Guidance for Industry" | March 08, 2018


 FDA guidance and CDER guidance for NDA and BLA

"The purpose of this guidance is to clarify circumstances under which the FDA’s Center for Drug Evaluation and Research (CDER) may refuse to file a new drug application (NDA) or supplemental NDA (21 CFR 314.101) or a biologics license application (BLA) or supplemental BLA (21 CFR 601.2) for a therapeutic biological product regulated by CDER and to underscore the importance of submitting a complete application to minimize the chance of a refuse-to-file (RTF) action by the FDA. In particular, this guidance focuses on the FDA’s policy for refusing to file an NDA under § 314.101 when the NDA is incomplete because it does not on its face contain information required under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 314.50. 

This guidance does not address scenarios in which an application is incomplete under § 314.50 because it does not on its face contain information required under sections 505 and 507 of the FD&C Act or 21 CFR 314.94. Other circumstances under which the FDA may refuse to file are described in § 314.101(d)(1), (2), and (4) through (9) and will not be discussed in this guidance.

This guidance does not address refusal to file of abbreviated new drug applications (ANDAs), and it does not address refusal to file of an NDA for the regulatory deficiencies described in § 314.101(e). This guidance is not applicable to BLA submissions for biological products regulated by the Center for Biologics Evaluation and Research. This guidance also does not discuss the details of the format of an application required by § 314.50 or § 601.2 (NDA or BLA format) nor content required under 21 CFR 54.4(c) (financial disclosure) (see the Appendix). Although missing or inadequate information to address the requirements under section 505(b) of the FD&C Act and § 314.50 can be the basis for refusal to file an NDA discussed in the guidance, the specific format requirements detailed in § 314.50 will not be further described in this guidance. Because administrative filing procedures are well understood, this guidance is limited to consideration of whether an application is incomplete on its face for purposes of refusal to file.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required." 

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d-Wise's Insight on HHS's Guidance

On December 13th, 2017, the FDA Office of New Drugs in the Center for Drug Evaluation and Research (CDER) released a draft guidance, Refuse to File: NDA and BLA Submissions to CDER, for public review and comment.  The comment period closed February 12th, 2018.  

Sponsor companies fear an FDA refuse-to-file (RTF) notice. As this relates to sponsor biometrics organizations, handwringing often occurs during the first 60 days regarding standardized study datasets with questions such as:

  • "Will the Reviewer request changes to our SDTM and ADaM datasets?"  
  • "Will the FDA ask us to up-version to the latest version of SDTM?"
  • "Will we need to map legacy trials to SDTM and ADaM?" 

Although the draft guidance does not explicitly reference standardized study datasets, it does state that an RTF may be issued if "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 consider 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." In our opinion, this could be inferred as a circuitous reference the FDA's Technical Rejection Criteria for Study Data. d-Wise sought additional clarification during the public comment period to clarify the intent of the guidance.

The draft guidance emphasizes the importance of agreements between the FDA and sponsor "regarding the content of a complete application...” d-Wise is of the opinion that this includes agreements such as the Study Data Standardization Plan (SDSP). The SDSP, referenced in the FDA's Study Data Technical Conformance Guide, documents the studies and planned standards that will be included in submissions.  In our experience assisting customers with their regulatory submissions, we find customers are concerned the FDA Reviewer may change their mind regarding study datasets despite agreements documented in the SDSP. 

RTFs are not intended to punish sponsor companies.  They help the FDA ensure the application is complete so that the Agency can ensure therapies will benefit patients. d-Wise understands sponsors will always fear an RTF.  However, we appreciate that the FDA is attempting to clarify their decision making processes and the criteria for receiving an RTF. If you are reading this blog and have not read the draft guidance, we suggest you do and comment as appropriate. It's in the best interest of your company and the patients that need new therapies.


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