Manual of Standard Operating Procedures and Policies

Regulatory - License Applications

Review of Product Labeling

SOPP 8412

Version #2

Date: March 20, 2008
  1. Purpose
    2.

    This SOPP outlines the general operating procedures for Center for Biologics Evaluation and Research (CBER) staff to use to administratively process and review draft and final product labeling submissions.

  2. Background
    3.

    Proper labeling of licensed products is a requirement of the Food, Drug and Cosmetic Act and the Public Health Service Act. Labeling must be reviewed as part of Biologics License Applications (BLA) or New Drug Applications (NDA), Abbreviated New Drug Applications (ANDA), supplements, and annual reports. This SOPP does not apply to products regulated as Pre-market applications (PMA) or 510(k).

    The mechanism for reporting changes to labeling varies according to the type of change and the change's potential for having an adverse effect on product identity, strength, quality, purity, or potency as described in 21 CFR 601.12 and 314.70. The reporting categories allowed by these regulations include several different administrative processes for label submission and review. For licensed drug and biologics subject to 21 CFR 314.70 and 601.12, respectively, changes to a product package label, container label, and package insert require either: (1) submission of a supplement with FDA approval needed prior to product distribution (PAS); (2) submission of a supplement with product distribution allowed at the time of submission of the supplement (CBE); or (3) submission of the final printed labeling in an annual report.

    In December 2003, FDA published final regulations (the Electronic Labeling Rule; ELR) requiring the submission of content of labeling in electronic format for marketing applications. The requirements of the rule can be found in 21 CFR 314.50(l)(1)(i) for NDAs, 314.94(d)(1)(ii) for ANDAs, 601.14(b) for BLAs and 314.81 (b) for annual reports. Blood component labeling is not required to be submitted in electronic format at this time (see preamble to this regulation); therefore blood components are currently exempted from aspects of this SOPP. Following publication of the final rule, FDA issued Guidance for Industry: Providing Regulatory Submissions in Electronic Format- Content of Labeling in April 2005. The publication of this guidance indicated that the electronic format by which content of labeling should be submitted was Structured Product Labeling (SPL) which is based on the extensible markup language (XML).

    In January 2006, FDA issued a final rule, the Physician Labeling Rule (PLR), which required labeling for BLA and NDA to conform with 21 CFR 201.56 and 201.57. The PLR revised the existing labeling regulations to require that the prescribing information of new and recently approved products include a cross-referenced “highlights” section and table of contents. It also required that the labeling be reordered and established minimum format requirements. The intent of the PLR was to make the prescribing information more accessible and informative for practitioners to improve risk and benefit communications and risk management. FDA has not defined prescribing requirements for blood components, therefore blood components are be exempt from this aspect of the SOPP.

    On September 27, 2007, the President signed the Food and Drug Administration Amendments Act (FDAAA), which includes the Prescription Drug User Fee Amendments of 2007 (PDUFA IV). In conjunction with the reauthorization of PDUFA, the FDA agreed to meet specific performance goals. These PDUFA goals are described in PDUFA Reauthorization Performance Goals and Procedures. Under the PDUFA IV goals, CBER agreed to develop procedures for review staff on how to notify applicants of planned review timelines for original NDA/BLA applications and efficacy supplements. Although non-PDUFA products are not subject to PDUFA goals, CBER strives to meet these timelines for non-PDUFA products, as resources allow.

  3. Policy
    4.

    General

    • "Labeling" consists of all printed material distributed with a product including package labels, container labels, package inserts, patient inserts, instructions for use, Medication Guides, and Dear Doctor letters.

    • “Content of Labeling” refers to the labeling required under 21 CFR 201.100(d) including all text, tables and figures (commonly referred to as the package insert or professional labeling).

    • SPL formatted content of labeling must be provided with original licensing applications along with a WORD-formatted version, except for labeling associated with blood and blood components. Labeling negotiations will be conducted using redline/strikeout function in WORD format. The WORD version requirement will be terminated when editing in SPL becomes more efficient.

    • Labeling may be either draft or final product labeling (FPL). FPL is generally submitted at the time of implementation, after approval of an original application or supplement, and may include changes approved in more than one submission. FPL will be assigned a submission tracking number (STN). FPL in SPL format will be required at time of approval or within 14 days of approval. FPL received as SPL will be transmitted to the National Library of Medicine (NLM).

    • Labeling may be either draft or final product labeling (FPL). FPL is generally submitted at the time of implementation, after approval of an original application or supplement, and may include changes approved in more than one submission. FPL will be assigned a submission tracking number (STN). FPL in SPL format will be required at time of approval or within 14 days of approval. FPL received as SPL will be transmitted to the National Library of Medicine (NLM).

    • All changes to product labeling will be considered a supplement to the applicant's BLA/NDA unless the change is a type that can be submitted in an annual report. 21 CFR 314.70 and 601.12 describe the types of labeling changes that may be submitted as final product labeling in annual reports (e.g. minor editorial). The applicant must identify the changes; CBER will review those changes and return comments.

    • Labeling supplements are assigned an STN.

    • Labeling that accompanies a new BLA/NDA, chemistry, manufacturing, and controls (CMC) or clinical efficacy supplement will be tracked and reviewed under the STN assigned to that submission.

    • The labeling revisions will also be subject to the provisions under FDAAA for Safety Labeling Changes and the Pediatric Research Equity Act (PREA).

    Review Time Frames

    Labeling review is performed as part of the complete review of the application or supplement. The review time frame depends on the designation of the application or supplement as priority or standard as defined in SOPP 8405, Complete Review and Issuance of Action Letters. A priority application or original efficacy supplement is reviewed in 6 months and a standard application or original standard efficacy supplement is reviewed in 10 months. All other labeling supplements are reviewed in 6 months.

    The passage of FDAAA requires that a target timeline be provided for conducting labeling review on new applications and that the applicant is apprised of this date in the Filing letter. In addition, FDAAA requires that proprietary name reviews be completed within 90 days when submitted in relation to an original marketing application (BLA/NDA) or 180 days when submitted under Investigational New Drug Application (IND). Additional timeframes may be applicable as Center targets for review and communication of labeling changes under the provisions for FDAAA Safety Labeling Changes.

    Label Changes (21 CFR 314.70 and 601.12)

    For changes to approved labeling received in paper format, changes must be clearly identified (e.g. redline/strikeout) and must include all the information necessary to support the change. For changes to approved labeling received in SPL format, a comparison to the previous version is required prior to the review in order to clearly identify changes.

    Label supplements for NDA/BLA are categorized per 21 CFR 314.70 and 601.12 as either a prior approval supplement (PAS), changes being effected supplement (CBE) or annual report (AR) and further guidance is provided for blood components in Guidance for Industry; Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture (August 2001).

  4. Responsibilities and Procedures
    5.

    Labeling in Original BLA and Supplements

      1. Receipt of Labeling Submissions in Marketing Applications and Supplement

        1. Document Control Center (DCC):

          • Receives, logs in and routes to all appropriate Offices all BLA/NDAs and extra reviewer copies. DCC will route the submission based on the product name as reported by the applicant on the Form FDA 356h.
          • The original copy of the submission (paper and/or electronic) will be maintained in DCC as an uncirculated record copy

        2. Regulatory Project Manager (RPM):

        Upon receipt of the labeling submission in the Product Office, the RPM will perform the following as applicable:

        1. Preliminary review to determine if the submission is correctly classified by the applicant as original application, PAS, CBE or AR. If the preliminary review indicates that the supplement was incorrectly categorized, the applicant will be informed in writing in the acknowledgement letter of the category correction or will be requested to make the change in an annual report. Confirmation of the submission classification will be communicated to the Electronic Document Room (EDR) team (edrteam@fda.hhs.gov) to ensure proper coding of the submission in the repository for SPL labeling as original application, PAS, CBE or AR. The proper coding of the submission is essential to ensure appropriate posting to the National Library of Medicine (NLM) by the labeling repository system following uploading of SPL. The labeling repository system will automatically post CBE and AR SPL labeling to the NLM following upload of the submission.

        2. Assign a Submission Tracking Number (STN) in the appropriate regulatory database (RMS-BLA for BLA and BLT for NDA).

        3. Assign the Review Schedule:

          • Original BLA/NDAs will be assigned a schedule type of Standard 10 or Priority 6.
          • Original efficacy supplements will be assigned a supplement type of PAS, and a schedule type of Standard 10 or Priority 6.
          • Labeling supplements will be assigned a supplement type of PAS or CBE, and a schedule type of Standard 6.
          • Note that in RMS-BLA Labeling for Whole blood and blood components has the schedule type “Blood bank/Source Plasma 6 months”

        4. Write an acknowledgement letter to the applicant providing the STN assignment. Acknowledgement letters should be written for all original BLA/NDA submissions, efficacy supplements and labeling supplements with the exception noted below.

          • These letters may optionally include the filing paragraph (considered filed on day 60 unless applicant notified otherwise).
          • Sign-off of these letters will be according to Office-specific policies and procedures.
          • The Filing letter will state the target date when the labeling discussions will take place.
          • The Office of Blood Research and Review (OBRR)/ Blood and Plasma Branch does not send out STN assignment or filing letters for stand-alone labeling supplements. The STN number is provided on the Review Checklists and Form 2567.
        1. EDR Team

        Upon receipt of confirmation of submission category (original, PAS, CBE, AR) the EDR team will be responsible for loading SPL into the labeling repository system and performing SPL technical file validation. Validation errors will be communicated to the RPM for communication to the applicant.

        1. Review of labeling:
          2.

        Original Applications and supplements will be reviewed according to Office specific policies and procedures. The following types of review are required during review of labeling:

        1. Content of Labeling Review

        Reviewer tools are available on FDA’s CDER Study Endpoint and Labeling Development (SEALD) website and SPL Resource page on the Data Council Website to aid in assessment of compliance.

        1. RPM

          • Reviews content of labeling to ensure compliance with PLR formatting.

        2. Clinical Reviewer

          • Reviews content of labeling to ensure compliance with PLR content requirement and other requirements with respect to clinical information (e.g., PREA requirements for labeling of all pediatric studies).
          • Reviews for accuracy of clinical information relative to the information provided in the application or supplement.
          • Identifies indexing data element terminology and codes.

        3. CMC Review

          • Reviews for accuracy of product information relative to the information provided in the application or supplement.

        4. APLB Review

          • The Office of Compliance and Biologics Quality (OCBQ)/ Advertising and Promotional Labeling Branch (APLB) reviews the content of labeling from a labeling comprehension and promotional perspective to ensure that it is not false or misleading.

        1. Review of Instruction Circular

        CBER clinical reviewers review the instruction circular to ensure compliance with 606.122

        • A Circular of Information for the Use of Human Blood and Blood Components (the “Circular”) has been developed by the major industry organizations representing blood establishments and is reviewed to ensure compliance with 21 CFR 606.122. CBER announces in guidance that the "Circular" is an acceptable standard and that it complies with the requirements and thereafter it is not required to be submitted or reviewed with each submission if the accepted version is in use. After CBER announcement of acceptance of this “Circular” in a guidance document, firms may submit use of it in their annual report if there are no changes to the Circular of Information.

        Review staff should expect to receive a new Instruction Circular in the following situations:

        • A firm may modify the “Circular” to contain facility specific information or have included additional products or cautions announced by the FDA. Depending on the type of information added, the submission of a modified Circular of Information may be a PAS, CBE or annual report.
        • When a firm submits a supplement for a new product and provides an instruction circular or indicates that the “Circular” has been modified, the submission is categorized as a PAS. CBER staff review of the circular is to ensure the content is in compliance with the regulations or that the modified “Circular” is consistent with the accepted standard Circular of Information. Any modifications that need closer review are identified.

        1. Proper (Established) Name Review

          1. RPM
        • Confirms proper name as recorded in appropriate regulatory database is correct.

        1. CMC Review

          • Reviews proper name to ensure consistency with product information provided in the application or supplement.
          • Assures compliance with naming conventions as established by US Adopted Name Council (USAN) or Office-specific policies if no USAN name is available.

        2. Clinical Review

          • Reviews for being informative to health care professionals.
        1. Proprietary (Trade) Name Review

          1. RPM
          • Confirms proprietary name is recorded in appropriate regulatory database.

        1. Clinical Review

          • Reviews proprietary name to ensure compliance with 21 CFR 201.10(c).

        2. APLB Review

          • Reviews proprietary name to ensure compliance with the regulations (according to SOPP 8001.4 Review of CBER Regulated Proprietary Names).
        1. Drug Listing Data Element Review
        1. CMC Review

          • Reviews for accuracy of product information relative to the information provided in the application or supplement and ensures correct coding of data elements.
          • Communicates errors in data element coding to applicant and provides correct coding consistent with the established terminology.

        1. Container/Carton Label Review

          1. CMC Review

            • Reviews for accuracy of product information relative to the information provided in the application or supplement.
            • Ensure compliance with label requirements as described in 21CFR Part 201 and 610.
        1. APLB Review

          • Reviews from a comprehension and promotional perspective, as well as from a safety perspective relative to possible medication errors.
          • Ensures compliance with label requirements as described in 21 CFR 202.
          • Blood and blood components use industry standardized labeling and therefore there is no APLB review.

        2. Clinical Review

          • Reviews format and content for being informative to health care professional.
        1. Labeling Supplements:
          2.

          • If a labeling change (or other change) is incorrectly submitted in an annual report or incorrectly categorized as a CBE, the RPM will promptly notify the applicant by telephone and letter, and request the applicant to submit a supplement or PAS, respectively. For labeling received in SPL, the RPM will immediately notify the EDR team that the labeling category is incorrect to ensure that the SPL is not posted to NLM as would be the case for SPL received as CBE or AR.

          • If, following review of the submission, the labeling change is acceptable, then the RPM returns the labeling to the applicant with a completed Form FDA 2567. If the labeling was submitted as draft labeling, the FDA 2567 should indicate that final printed labeling should be submitted at the time of implementation. If the labeling was submitted as FPL, then the FDA 2567 should indicate that the labeling has been placed on file. For labeling received in SPL, the RPM notifies the EDR team that the labeling change is approved and the labeling category can be changed to FPL. The EDR team will upload the FPL SPL to the labeling repository for posting to NLM.

          • If, following review of the submission, the labeling change is not acceptable, then the RPM returns the labeling to the applicant with comments on a completed Form FDA 2567. Subsequent revised draft labeling will be tracked and filed as correspondence (3rd level STN).

          • For Annual Reports, processing will be in accordance with SOPP 8411.1: Changes to an Approved Application - Administrative Handling and Review of Annual Reports with the following provisos:
            • Annual reports will be assigned a second level STN. If draft labeling is submitted, the special characteristic field of RMS-BLA should be completed using the field value "Final Printed Labeling".
            • The submitted labeling will remain in the annual report.
            • If the submitted labeling does not represent a change, it does not need to be reviewed or returned with comments to the applicant. For labeling submissions in SPL, the applicants are requested to refrain from submitting SPL in AR if there are no changes.

        2. Communications of labeling review outcomes:
          3.

        The Form FDA-2567 will be used as a vehicle for returning labeling comments to the applicant for labeling received in paper format. Comments can be returned in conjunction with a letter (information request, or complete response, or approval), faxed, or by other accepted means of electronic communications and documented consistent with SOPP 8401: Administrative Processing of Biologics License Applications (BLA).

        1. Communication of Labeling changes by the RPM

          • If labeling is returned in a letter, the appropriate letter value will be entered in the appropriate database ( i.e., RMS-BLA for BLAs). If labeling is returned via fax, then the entry in RMS-BLA should read "Telecon/Other/fax-labeling comments". If labeling is returned via secure e-mail, then the entry in RMS-BLA should read "Telecon/Other/e-mail-labeling comments.
          • Revised draft labeling submitted by the applicant will be processed as an amendment to the pending application or supplement and assigned a third level STN. All fax communications from the applicant should be processed as per SOPP 8113 Handling of Regulatory Faxes.
          • For blood and blood components, the Form FDA 2567 serves as the approval letter for the submission and is sent to the applicant. A copy of the label review checklists and labels/labeling is also returned to the applicant.
        1. Archiving of labeling documentation:
        1. Draft labeling with all accompanying reviews and correspondence will remain with the application/supplement administrative file and will be organized chronologically with other correspondence in the file.

        2. Final Labeling

          • The approval letter will request that the applicant submit final approved content of labeling in SPL format and final printed container/carton labels at the time of implementation, with Form FDA-2567 completed. An XML-formatted electronic copy (SPL), as well as ten paper copies of the package inserts, patient insert, or Medication Guide, and five copies of other product labeling may be requested.
          • Upon receipt, labeling is to be entered into the appropriate regulatory database and assigned as a second level STN submission. The submission should be entered with a Special Characteristic value of "Final Printed/Product Labeling" into the Submission Screen. In the Submission Category area, the type of labeling (e.g., container, carton, package insert) should be entered.
          • Documents should be filed according to the appropriate DCC Procedure Guide.
          • The RPM will notify the EDR team that the labeling is approved and ready to be uploaded and posted to NLM.
          • For significant approvals (e.g. efficacy supplements, important new warnings) copies of the final printed package insert will be distributed in accordance with CBER SOPP 8401: Administrative Processing of Biologics License Application (BLA).

  5. Effective Date
    6.

    March 20, 2008

  6. References

21 CFR Parts201, 201.10( c), 201.56, 201.57, 201.100(d)(3), 202.1, 299.4, 314.50(l)(1)(i), 314.70, 314.81 (b), 314.94(a)(8), 601.12, 601.14(b), 610, 606,122,

Food and Drug Administration Amendments Act (FDAAA), September 2007

PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2008 Through 2012, an enclosure to the transmittal letter from Michael O. Leavitt, Secretary of Health and Human Services, to John D. Dingall, Chairman, committee on Energy and Commerce, House of Representatives, dated September 27, 2007

Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products, (commonly referred to as the Physician Labeling Rule [PLR)) January 2006

Requirements for Submission of Labeling for Human Prescription Drugs and Biologics in Electronic Format (commonly referred to as the Electronic Labeling Rule); December 2003

Pediatric Research Equity Act (PREA) December 2003

Guidance for Industry: Providing Regulatory Submissions in Electronic Format- Content of Labeling (April 2005)

Guidance for Industry; Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture (August 2001).

SOPP 8001.4: Review of CBER Regulated Proprietary Names

SOPP 8401: Administrative Processing of Biologics License Applications (BLA)

SOPP 8405: Complete Review and Issuance of Action Letters

SOPP 8411.1: Changes to an Approved Application - Administrative Handling and Review of Annual Reports

CDER Study Endpoint and Labeling Development (SEALD) website on FDA’s Intranet

SPL Resource page on the Data Council Website on FDA’s Intranet

  1. History

    2.

    Comment / Revision
    Approved By
    Approval Date
    Version Number
    Comment
    L. Falk/RMCC Robert Yetter, PhD
    Mar 20, 2008
    2
    		Update to include Physician’s Labeling Rule;
    Submission of labeling in Structured Product Labeling Format
      Robert Yetter, PhD
    Dec 23. 2002
    1
    		 Original version of SOPP
 
Updated: March 20, 2008