Vaccines, Blood & Biologics

SOPP 8404: Refusal to File Procedures for Biologics License Applications, New Drug Applications and Efficacy Supplements

Version: 4
Effective Date: July 10, 2015

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  1. Purpose
    1. This standard operating policy and procedure (SOPP) serves as a guide for Center for Biologics Evaluation and Research (CBER) staff to follow once a Refuse To File (RTF) determination is made for a Biologics License Application (BLA) or Efficacy Supplement (21 CFR 601.2) or New Drug Application (NDA) or supplemental NDA (21 CFR 314.101(d)(1)-(9)).

     

  2. Scope
    1. This SOPP applies to BLA, NDA or efficacy supplements for which an RTF decision was made.
    2. Instructions on the process for filing an application once a decision is made to file is described in SOPP 8401: Administrative Processing of Original Biologics License Applications (BLA) and New Drug Applications (NDA) or in SOPP 8401.2: Administrative Processing of Biologics License Application Supplements (BLSs) [Except Blood, Blood Components, and Source Plasma].
    3. This SOPP does not apply to BLAs subject to the Medical Device User Fee Act (MDUFA) or Abbreviated New Drug Applications subject to the Generic Drug User Fee Act (GDUFA).

     

  3. Background
    1. RTF is an important regulatory tool to help CBER avoid unnecessary review of incomplete applications. Incomplete applications can lead to multiple-cycle reviews and inefficient use of CBER resources and may also delay the review of more complete applications from other applicants. CBER also believes an RTF action can allow an applicant to begin repair of critical deficiencies in the application far sooner than if the deficiencies were identified much later in a complete review action and may lead to more rapid approval of safe and effective products.  Applications accepted for filing should be sufficiently complete to permit a meaningful review.
    2. Applications are expected to be complete when received by the Agency. Incomplete applications will be subject to an RTF decision.
    3. Resources such as discipline-specific filing checklists were developed to enable a timely and thorough filing review of applications, to provide consistency in applying our RTF authority, and to enhance documentation of deficiencies for the RTF letter.
    4. Note: Identifying RTF deficiencies versus Complete Review deficiencies are described in more detail in Appendix B of this SOPP.

     

  4. Definitions
    1. RTF Issues – Application deficiencies that serve as the basis for an RTF decision.

     

  5. Policy
    1. RTF decisions are made on applications that do not, on their face, contain information required under section 351 of the Public Health Services Act; the Federal Food, Drug, and Cosmetic Act; or in the FDA regulations [e.g., § 601.2 for BLA and §314.50 for NDA]. RTF decisions can therefore be based on findings such as:
      1. administrative incompleteness of an application, such as clear omission of information or sections of information required;
      2. scientific incompleteness of an application, such as omission of critical data, information or analyses needed to evaluate safety, purity and potency or provide adequate directions for use; and
      3. inadequate content, presentation, or organization of information in an application such that substantive and meaningful review is precluded, such as illegibility; failure to translate portions of the application into English; data tabulations (line listings) or graphical displays that are uninterpretable; failure to reference the location of individual data and records in summary reports; absence of protocols for clinical trials; omission of critical statistical analyses or the analysis of a study as planned in the protocol (as opposed to a different, post-hoc analysis); or due to technically deficient electronic submission.
    2. CBER's initial decision on whether or not to file an applicaon or supplement will be based upon a threshold determination as to whether the information submitted to support licensure or approval is sufficiently complete to permit a substantive and meaningful review.
    3. For products submitted under the PDUFA V Program, a pre-BLA/NDA meeting occurs whereby the FDA and the applicant agree on the content of a complete application for the proposed indication(s) and identify minor components that may be submitted no later than 30 calendar days after receipt of the original application. Applications are expected to be complete when received by the Agency. Incomplete applications, including applications with minor components not received within the 30 calendar days after receipt of the original application, will be subject to an RTF decision.

     

  6. Responsibilities
    1. Branch/Lab Chief, Division Director – Reviews the reviewer’s recommendations; concurs/does not concur on recommendation. Writes separate memo for a non-concurrence
    2. Chair/Regulatory Project Manager (RPM) – Drafts and finalizes Filing Meeting Summary and Filing or RTF letter; manages RTF process; ensures issuance of the Filing/RTF letter to the applicant
    3. Office Director, Deputy Office Director – the Signatory Authority who signs RTF letters
    4. Review Committee Members – Reviews submission, recommends fileability of submission, documents recommendation in the filing checklist or a filing review memo, discusses the filability of application with management; reviews draft meeting summary and draft Filing or RTF letter

     

  7. Procedures
    1. Prior to the Filing Meeting
      1. Review the submission as described in JA 910.06: Completing a Filing Review [Review Committee Members]
      2. Notify the Chair, RPM, and supervisors (Branch/Lab Chief, Division Director) of the potential of a RTF recommendation [Review Committee Members]
      3. Ensure that management is notified immediately upon discovering that a RTF recommendation may be made [Chair/RPM]
      4. Complete the filing checklists, summarize all potential review deficiencies and RTF items in letter ready format in the appropriate section of the checklist or in the filing review memo [Review Committee Members]
      5. Email the checklists, with the appropriate management copied, to the Chair and RPM prior to the filing meeting [Review Committee Members]
      6. Discuss and recommend whether the submission should or should not be filed during the filing meeting [Review Committee Members, Branch/Lab Chief, Division Director, Office Director]
      7. Invite the Associate Director for Review Management (ADRM) to the filing meeting only if a RTF is anticipated [Chair/RPM]
      8. Decide on whether the submission should or should not be filed at the filing meeting [Review Committee Members, Branch/Lab Chief, Division Director, Office Director, ADRM] Note: If ADRM is unable to attend the filing meeting, discuss the RTF decision with him/her prior to sending the draft RTF letter around for office comment.
    2. After Filing Meeting - Filing Checklists
      1. Update the filing checklist or review memo, if needed, and include a rationale if recommending an RTF decision in the appropriate section of the filing checklist or review memo. The RTF recommendation must include a list of missing, incomplete, or inaccessible information [Review Committee Members]
      2. Sign the filing checklist or review memo; send for supervisory review and concurrence [Review Committee Members]
      3. Perform a secondary review of the signed checklist to determine concurrence on the fileability, rationale, and any letter ready comments. Any non-concurrence must be accompanied by a written explanation [Branch/Lab Chief, Division Director]
      4. Prepare a written justification, if the reviewer’s recommendation is not accepted, enter into RMS-BLA and upload to EDR [Branch/Lab Chief, Division Director]
      5. Certify the filing checklist after secondary review is completed, enter in RMS-BLA and upload to EDR [Review Committee Members]
    3. After Filing Meeting – Meeting Summary and RTF Letter
      1. Draft the Filing Meeting Summary and document the final decision. The final decision should include the rationale for not filing the submission and a list of missing, incomplete, or inaccessible information [Chair]
      2. Draft the Refuse to File letter using the current CBER letter template. Please refer to CBER’s Review Letter Templates on CBER’s Intranet Web page for the most recent approved template. Include the following: [RPM]
        1. the deficiencies that form the basis for the RTF decision
        2. the option to protest the Agency’s decision and request that CBER file and review the application over protest (FOP), as well as a web site link to SOPP 8404.1: Procedures for Filing an Application When the Applicant Protests a Refusal to File Action (File Over Protest)
      3. Send draft Filing Meeting Summary and RTF Letter to Review Committee Members, Branch/Lab Chief, Division Directors and Office Directors for concurrence [RPM]
      4. Review Filing Meeting Summary and RTF Letter for accuracy and completeness and provide feedback to RPM [Review Committee Members, Branch/Lab Chief, Division Directors, Office Directors]
      5. Obtain and concurrence approval of Filing Meeting Summary and RTF Letter. Signature authority of RTF Letter is the Office Director or designee [RPM]
      6. Enter signed and certified Filing Meeting Summary and RTF Letter into RMS-BLA and upload to EDR. [RPM] Ensure that the RTF letter is mailed to the applicant within 60 days of the CBER receipt date [RPM]
      7. Send a notification of the RTF decision and include the RTF Letter, Filing Meeting Summary, and review checklists and memos to all relevant Office Directors, Associate Director For Review Management and the Center Director [RPM
      8. Return Documents to the Document Control Center (DCC) after a RTF is issued according to DCC Procedure Guide #8  Procedure for Filing Final Action Packages Containing Paper FDA Correspondence For Marketing Applications – Including Multiple Product or DCC Procedure Guide #23 Procedure for Filing Final Action Packages Containing Electronic FDA Communication for Marketing Applications as applicable [RPM, Review Committee Members]

     

  8. Appendices
    1. Appendix A: Guidance Documents on Refusal to File New Drug Applications; Availability [Federal Register Notice, vol. 58, N0. 137, July 20, 1993, 38770-38771]
    2. Appendix B: Refusal to File (RTF) versus Complete Review

     

  9. References
    1. References below are located on CBER’s Intranet Web Page (unless otherwise noted)
      1. JA 910.06, Completing a Filing Review
      2. DCC Procedure Guide 20, Procedure For Returning Pending License Or Application Materials To DCC For Storage
      3. DCC Procedure Guide #23 Procedure for Filing Final Action Packages Containing Electronic FDA Communication for Marketing Applications
    2. Web links to the references below can be found in the list following the History Table
      1. SOPP 8401: Administrative Processing of Original Biologics License Applications (BLA) and New Drug Applications (NDA)
      2. SOPP 8401.2: Administrative Processing of Biologics License Application Supplements (BLSs) [Except Blood, Blood Components, and Source Plasma]
         
      3. SOPP 8404.1: Procedures for Filing an Application When the Applicant Protests a Refusal to File Action (File over Protest)
         

     

  10. History
Written/ RevisedApproved ByApproval DateVersion NumberComment
Sandra MenziesChristopher Joneckis, PhDJuly 2, 20154Update to use Filing Checklists to support RTF
RMCC/Lydia FalkRobert A. Yetter, PhDAugust 22, 20073Corrects link to CBER’s RTF philosophy as per Federal Register notice
Leonard WilsonRobert A. Yetter, PhDOctober 2, 20022Clarifies roles and responsibilities, adds reference to FOP procedures.
CBER Application Policy Task ForceMichael BeatriceNovember 1, 19931Reissued as SOPP 8404 in August 1997. No change to Guide Content (OD-R-2-93)

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