• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

  • Print
  • Share
  • E-mail

SOPP 8404: Refusal to File Procedures for Biologic License Applications

Version #3

Effective Date: August 27, 2007


  1. Purpose
  1. The purpose of this document is to describe the policies and procedures for staff to follow to determine if a Biologics License Application (BLA) or its supplement meets the standards established to initiate a meaningful review. It does not establish standards for technical merit of the application but does follow the regulatory requirement that all pertinent information be present at the time the application is submitted (21 CFR 601.2). The same procedures and criteria are used for assessing BLA supplements.

     

  1. Background
  1. Regulatory

    21 CFR 601.2:

    • states that an application for license shall not be considered as filed until CBER has received all pertinent information and data from the manufacturer; and
    • lists general categories of information required to be submitted in any BLA.

    Refusal to File (RTF) decisions are made on applications that do not, on their face, contain information required under section 351 of the Public Health Service Act; the Federal Food, Drug, and Cosmetic Act; or in FDA regulations [e.g., 21 CFR 601.2 ]. RTF decisions can therefore be based on findings such as:

    • administrative incompleteness of an application (i.e., clear omission of information or sections of information required);
    • scientific incompleteness of an application (i.e., omission of critical data, information or analyses needed to evaluate safety, purity and potency or provide adequate directions for use [21 CFS 601.2]). The concept of "potency" of a biological product includes clinical evidence of effectiveness, demonstrated by adequate and well-controlled clinical trial(s) or acceptable alternative scientific methods;
    • inadequate content, presentation, or organization of information in an application such that substantive and meaningful review is precluded (e.g., 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 (1).

    In summary, CBER's initial decision on whether or not to file a BLA or supplement will be based upon a threshold determination as to whether the information submitted to support licensure is sufficiently complete to permit a substantive and meaningful review.

    Refusal to File (RTF) vs Complete Review

    In general, a RTF is based on omissions of clearly necessary information (e.g., information required under the statute or regulations) or omissions or inadequacies so severe as to render the application incomplete on its face and where the omissions or inadequacies are obvious, at least once identified, and not a matter of interpretation or judgment about the meaning of data submitted. An RTF is not a final determination concerning potential approvability; it can be an early opportunity for the applicant to develop a complete application, but will delay, at least for a time, a full review of the application. Additionally, if the applicant submits a filing based on a study or studies deemed inadequate during the Investigational New Drug (IND) review process and which remained uncorrected after the inadequacies were clearly communicated to the applicant by CBER, then CBER may refuse to file the application. Likewise, RTF may apply if the application contains other uncorrected deficiencies (e.g., manufacturing or product specifications) which were clearly communicated to the applicant before submission of the application or contain technical deficiencies for electronic submissions, sufficient to require resolution before a meaningful review could occur. The RTF is not an appropriate vehicle for dealing with complex issues and close judgments on such matters as balancing risks and benefits, magnitude of clinical effect, acceptability of a plausible surrogate marker, or nuances of study design (although obviously inadequate designs may lead to RTF, see below).

    By contrast, issuance of a Complete Response (CR) Letter (after a complete review) is generally based on critical omissions of data or analyses as well as on an adverse judgment about the data, conclusions, rationale, etc., presented in the application. For example, a Complete Response Letter could be issued based on the conclusion that:

    • effectiveness has not been demonstrated,
    • an analysis was incorrectly carried out,
    • clinical trials were poorly designed or conducted,
    • safety has not been adequately demonstrated, or
    • outstanding compliance issues remain.

    These judgments would not serve as the basis for RTF unless the deficiencies were so severe as to render the application incomplete on its face.

    Review Process Efficiency

    Clear and well-understood procedures are necessary to ensure an efficient review and for identification of those submissions that should be classified as RTF. These procedures should be consistent with the Filing Regulations in 21 CFR 601.2; the review timelines and comprehensive action letters used in implementing the Prescription Drug User Fee Act of 1992 (PDUFA), et seq.; and CBER's managed review process.

    CBER's philosophy as articulated in the Federal Register (FR vol 58, No 137) (Appendix 1) and consistent with the Center for Drug Evaluation and Research (CDER) RTF guidance document (2) supports that initiating review of an incomplete or inadequate application is inherently inefficient and ultimately extends review time.

    • The review of deficient applications often involves several cycles of Food and Drug Administration (FDA) - applicant correspondence, consuming a disproportionate share of agency resources in extra review, letters, and meetings.
    • These delays not only extend the review time associated with the deficient application but also potentially delay the review of more complete applications from other applicants.
    • Thus, to help ensure equity and consistency of FDA review time for the industry, as well as to optimally utilize agency resources, applications accepted for filing should be sufficiently complete to permit a meaningful review.
    • An application that has required major repair during review will usually appear to be one with prolonged review time, even if actual review is efficient and swift. Given the strong criticism the agency has received for prolonged approval times, it is important to try to ensure that, as much as possible, review times reflect the period of agency effort, not the time needed for the applicant to repair an inadequate application.
    • RTF is not necessarily a final decision regarding the scientific/medical merits of the application; instead, it is an early signal to the applicant that the application has omissions or inadequacies so severe as to render the application incomplete on its face or to introduce significant impediments to a prompt and meaningful review (e.g., the need for substantial amounts of additional data and analyses). This message is transmitted early so that "repairs" can be promptly initiated by the applicant.

     

  1. Policy
  1. General

    This SOPP applies to PDUFA and non-PDUFA Biologics License Applications and supplements, whether sourced from a paper or electronic submission.

    RTF should be reserved for applications with deficiencies that

    • make the application obviously inadequate;
    • could not be reviewed without major repair; or
    • render review unreasonably difficult in that it would consume a disproportionate amount of agency resources to correct deficiencies.

    It is CBER policy that RTF practices should be consistent across all review offices and divisions. To assure consistency, CBER will conduct periodic examinations of all refusal to file actions. The purpose of this periodic review is not to reconsider individual decisions (the actions and responses would have occurred well before the examination). Rather, the review is intended to examine the RTF experience considering, among other things, consistency across the Center in applying the guidance, the need for any additional guidance for applicants on BLA content or format, and any need for modification of the RTF guidance.

    Basis for a RTF under 21 CFR 601.2 Applications for Biologics Licenses: Procedures for filing.

    A RTF decision may be made in the absence of any of the following:

    • Data derived from nonclinical laboratory and clinical studies that demonstrate that the manufactured product meets prescribed standards of safety, purity and potency [The concept of "potency" of a biological product includes a demonstration of clinical potency, i.e., effectiveness];
    • A full description of manufacturing methods;
    • Data establishing stability of the product through the dating period;
    • Identification by lot number and submission of sample (s) representative of the product to be introduced or delivered for introduction into interstate commerce;
    • Summaries of results of tests performed on the lot(s) represented by the sample(s);
    • Specimens of the labels, enclosures, and containers, and if applicable Medication Guide, proposed to be used for the product;
    • An environmental assessment or claim for exclusion with supporting information;
    • Financial certification or disclosure statements, or both, for clinical investigators as required by 21 CFR Part 54; or
    • List of all manufacturing sites, including contract facilities.

    In addition to the above, the following statements should be included in the application (as appropriate) with respect to the requirement to submit data derived from nonclinical laboratory and clinical studies:

    • For each non-clinical laboratory study, either a statement that the study was conducted in compliance with the requirements set forth in 21 CFR Part 58 or, if the study was not conducted in compliance with such regulations, a brief statement justifying the non-compliance.
    • A statement with regard to each clinical investigation involving human subjects that it either was conducted in compliance with the requirements in 21 CFR Part 56, or was not subject to such requirements in accordance with 21 CFR 56.104 and 56.105 and was conducted in compliance with requirements for informed consent in 21 CFR Part 50.

    File Over Protest

    Our letter notifying the applicant of the RTF decision provides the option to protest the Agency's decision and request that CBER file and review the application over protest (FOP), as well as a website link to our procedure (SOPP 8404.1: Procedures for Filing an Application When the Applicant Protests a Refusal to File Action (File Over Protest), Appendix 2).

    Returning Documents after a RTF was issued

    The record copy of applications or supplements deemed RTF are maintained in the Document Control Room (DCC). Copies other than the administrative record of applications or supplements that have been deemed to be incomplete or inadequate for filing may be returned to the submitting manufacturer. The manufacturer may retrieve the document at their expense; copies will not be packed for shipping by the Agency. If the submitting manufacturer does not wish the return of the copies, the copies will be destroyed.

     

  1. Responsibilities and Procedures
  1. Product Offices

    • RTF authority is delegated to the review Divisions for all BLAs and BLA supplements.
    • Divisions will evaluate and meet to discuss whether the application will be filed using Managed Review Process procedures.
      • Each discipline reviewer will communicate their filing recommendation verbally during the filing meeting or in writing through a filing review memorandum or email.
        • If it has been determined that a filing meeting will not take place, the reviewers will forward their filing recommendation and deficiencies identified with letter ready comments to the Regulatory Project Manager (RPM).
        • If the discipline reviewer's recommendation is to RTF the application, the reviewer will submit a filing review memorandum and obtain supervisory concurrence.
        • The Divisions will consult with their Office Director on RTF decisions.

    Regulatory Project Manager

    • The RPM will collate letter ready comments and prepare a draft letter, as appropriate, by day 45 to ensure adequate time for review committee review of the refuse to file letter.
    • The RPM will ensure that a record is prepared of any internal meeting that leads to a refuse to file decision. This documentation will ordinarily consist of the following:
      • Meeting summaries. Meeting summaries will include any review memoranda and a listing of decisions reached.
      • The meeting summary must record why the application was found to be defective and thus a RTF decision made
    • The RPM will prepare a Filing Letter advising the applicant of the decision. If the filing decision is to RTF, the filing letter will also include the deficiencies that form the basis for the RTF decision.
    • Issue a Filing letter within 60 days of the receipt of the application.
    • The RPM will send copies of the Filing Letter to the review team. If the application is to be RTF, the RPM will also send the RTF letter and associated meeting summaries and review memoranda to all relevant Office Directors and the Center Director.

     

  1. References
    • Guidance for Industry: Providing Regulatory Submissions in Electronic Format - Receipt Date
    • New Drug Evaluation Guidance Document: Refusal to File, July 12, 1993
    • SOPP 8404.1, Procedures for Filing and Application When the Applicant Protests a Refusal to File Action (File over Protest)
  2. Appendices

    Appendix 1: Federal Register Notice, vol 58, No. 137, July 20, 1993, 38770-38771
     
  3. Effective Date

    August 27, 2007
     
  4. History
  1. Written/RevisedApprovedApproval DateVersion NumberComment
    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)